Stabilised insulin compositions

ABSTRACT

The present invention provides pharmaceutical compositions comprising insulin and novel ligands for the His B10  Zn 2+  sites of the R-state insulin hexamer. The resulting preparations have improved physical and chemical stability.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Application no.PCT/DK03/0931 filed Dec. 22, 2003, to which priority under 35 U.S.C. 120is claimed, the contents of which are fully incorporated herein byreference; this application also claims priority under 35 U.S.C. 119 ofDanish application no. PA 2002 01991 filed Dec. 20, 2002 and U.S.application No. 60/439,382 filed Jan. 10, 2003, the contents of each ofwhich are fully incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates to insulin compositions stabilised by addingligands for the His^(B10) Zn²⁺ sites of the R-state insulin hexamer, aswell as methods for preparation and use of such preparations.

BACKGROUND OF THE INVENTION

Diabetes is a general term for disorders in man having excessive urineexcretion as in diabetes mellitus and diabetes insipidus. Diabetesmellitus is a metabolic disorder in which the ability to utilize glucoseis partly or completely lost.

Since the discovery of insulin in the 1920's, continuous strides havebeen made to improve the treatment of diabetes mellitus. To help avoidextreme glycaemia levels, diabetic patients often practice multipleinjection therapy, whereby insulin is administered with each meal. Manydiabetic patients are treated with multiple daily insulin injections ina regimen comprising one or two daily injections of a protracted insulincomposition to cover the basal requirement, supplemented by bolusinjections of rapid acting insulin to cover the meal-relatedrequirements.

Insulin compositions having a protracted profile of action are wellknown in the art. Thus, one main type of such insulin compositionscomprises injectable aqueous suspensions of insulin crystals oramorphous insulin. Typically, the insulin in these compositions isprovided in the form of protamine insulin, zinc insulin or protaminezinc insulin

Soluble, rapid acting insulin compositions usually comprise insulin,insulin analogue or insulin derivative together with zinc ion, phenolicpreservative, isotonicity agent, and a buffer substance. In addition,the preparation may optionally contain some salts and/or surfactants.Such preparations contain insulin in the form of an R-state hexamer.

Insulin Allostery.

The insulin hexamer is an allosteric protein that exhibits both positiveand negative cooperativity and half-of-the-sites reactivity in ligandbinding. This allosteric behaviour consists of two interrelatedallosteric transitions designated L^(A) ₀ and L^(B) ₀, threeinter-converting allosteric conformation states (eq. 1), L^(A) ₀ L^(B) ₀T₆ ⇄ T₃R₃ ⇄ R₆ equation (1)designated T₆, T₃R₃, and R₆ and two classes of allosteric ligand bindingsites designated as the phenolic pockets and the His^(B10) anion sites.These allosteric sites are associated only with insulin subunits in theR conformation.Insulin Hexamer Structures and Ligand Binding.

The T- to R-transition of the insulin hexamer involves transformation ofthe first nine residues of the B chain from an extended conformation inthe T-state to an alpha-helical conformation in the R-state. Thiscoil-to-helix transition causes the N-terminal residue, Phe^(B1), toundergo an ˜30 Å change in position. This conformational change createshydrophobic pockets (the phenolic pockets) at the subunit interfaces(three in T₃R₃, and six in R₆), and the new B-chain helices form 3-helixbundles (one in T₃R₃ and two in R₆) with the bundle axis aligned alongthe hexamer three-fold symmetry axis. The His^(B10) Zn²⁺ in each R₃ unitis forced to change coordination geometry from octahedral to eithertetrahedral (monodentate ligands) or pentahedral (bidentate ligands).Formation of the helix bundle creates a narrow hydrophobic tunnel ineach R₃ unit that extends from the surface ˜12 Å down to the His^(B10)metal ion. This tunnel and the His^(B10) Zn²⁺ ion form the anion bindingsite. Ligands for the His^(B10) Zn²⁺ sites of the R-state insulinhexamer have been disclosed in U.S. Pat. No. 5,830,999.

Hexamer Ligand Binding and Stability of Insulin Compositions.

The in vivo role of the T to R transition is unknown. However, theaddition of allosteric ligands (e.g. phenol and chloride ion) to insulincompositions is widely used. Hexamerization is driven by coordination ofZn²⁺ at the His^(B10) sites to give T₆. Following subcutaneousinjection, some dilution of the depot will take place over time and theligands of soluble hexamers most likely diffuse away from the proteinrelatively rapidly. This is probably due to one or more phenomenaincluding the binding of Zn²⁺ by surrounding tissue and albumin, therelatively larger space available for diffusion of the hydrophobicphenolic preservatives, and the generally larger diffusion coefficientscharacteristic of the smaller sized molecules.

Insulin compositions are usually stored for extended periods of timee.g. in vials or cartridges. Furthermore, insulin pumps are becomingmore widely used, which places an additional demand on the chemical andphysical stability of the insulin composition due to the elevatedtemperatures and physical stress these preparations are exposed to.There is thus a need for insulin compositions that are more physicallyand chemically stable. It has been found that stabilising Zn²⁺-siteligands may be added to insulin compositions to improve theseproperties.

SUMMARY OF THE INVENTION

The present invention provides pharmaceutical compositions comprisinginsulin and novel ligands for the His^(B10) Zn²⁺ sites of the R-stateinsulin hexamer. The ligands belong to different subclasses ofcompounds, e.g. benzotriazoles, 3-hydroxy 2-napthoic acids, salicylicacids, tetrazoles, thiazolidinediones, 5-mercaptotetrazoles, or4-cyano-1,2,3-triazoles. The insulin may be rapid-acting. The insulinmay be selected from human insulin, or an analogue or derivativethereof. The formulation may also comprise a phenolic compound, anisotonicity agent, and buffer. Also claimed are methods of treating type1 or 2 diabetes comprising administration of a pharmaceuticalcomposition of the invention.

DESCRIPTION OF THE DRAWINGS

FIGS. 1-8 show ThT assays of various combinations of insulinformulations and ligands of the invention.

FIG. 9 shows disappearance rate of various combinations of insulinformulations and ligands of the invention from the subcutaneous depotfollowing injection in pigs.

FIGS. 10-14 show reverse phase chromatography of various combinations ofinsulin formulations and ligands of the invention.

DEFINITIONS

The following is a detailed definition of the terms used to describe theinvention:

“Halogen” designates an atom selected from the group consisting of F,Cl, Br and I.

The term “alkyl” as used herein represents a saturated, branched orstraight hydrocarbon group having the indicated number of carbon atoms.Representative examples include, but are not limited to, methyl, ethyl,n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl and the like.

The term “alkylene” as used herein represents a saturated, branched orstraight bivalent hydrocarbon group having the indicated number ofcarbon atoms. Representative examples include, but are not limited to,methylene, 1,2-ethylene, 1,3-propylene, 1,2-propylene, 1,4-butylene,1,5-pentylene, 1,6-hexylene, and the like.

The term “alkenyl” as used herein represents a branched or straighthydrocarbon group having the indicated number of carbon atoms and atleast one double bond. Examples of such groups include, but are notlimited to, vinyl, 1-propenyl, 2-propenyl, iso-propenyl, 1,3-butadienyl,1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl,2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl,2-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl and the like.

The term “alkynyl” as used herein represents a branched or straighthydrocarbon group having the indicated number of carbon atoms and atleast one triple bond. Examples of such groups include, but are notlimited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl,2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 2,4-hexadiynyl and the like.

The term “alkoxy” as used herein refers to the radical —O— alkyl,wherein alkyl is as defined above. Representative examples are methoxy,ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentoxy,isopentoxy, hexoxy, isohexoxy and the like.

The term “cycloalkyl” as used herein represents a saturated, carbocyclicgroup having the indicated number of carbon atoms. Representativeexamples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl and the like.

The term “cycloalkenyl” as used herein represents a non-aromatic,carbocyclic group having the indicated number of carbon atoms containingone or two double bonds. Representative examples are 1-cyclopentenyl,2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl,3-cyclohexenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2-cyclooctenyl,1,4-cyclooctadienyl and the like.

The term “heterocyclyl” as used herein represents a non-aromatic 3 to 10membered ring containing one or more heteroatoms selected from nitrogen,oxygen and sulphur and optionally containing one or two double bonds.Representative examples are pyrrolidinyl, piperidyl, piperazinyl,morpholinyl, thiomorpholinyl, aziridinyl, tetrahydrofuranyl and thelike.

The term “aryl” as used herein is intended to include carbocyclic,aromatic ring systems such as 6 membered monocyclic and 9 to 14 memberedbi- and tricyclic, carbocyclic, aromatic ring systems. Representativeexamples are phenyl, biphenylyl, naphthyl, anthracenyl, phenanthrenyl,fluorenyl, indenyl, azulenyl and the like. Aryl is also intended toinclude the partially hydrogenated derivatives of the ring systemsenumerated above. Non-limiting examples of such partially hydrogenatedderivatives are 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl and thelike.

The term “arylene” as used herein is intended to include divalent,carbocyclic, aromatic ring systems such as 6 membered monocyclic and 9to 14 membered bi- and tricyclic, divalent, carbocyclic, aromatic ringsystems. Representative examples are phenylene, biphenylylene,naphthylene, anthracenylene, phenanthrenylene, fluorenylene, indenylene,azulenylene and the like. Arylene is also intended to include thepartially hydrogenated derivatives of the ring systems enumerated above.Non-limiting examples of such partially hydrogenated derivatives are1,2,3,4-tetrahydronaphthylene, 1,4-dihydronaphthylene and the like.

The term “aryloxy” as used herein denotes a group —O-aryl, wherein arylis as defined above.

The term “aroyl” as used herein denotes a group —C(O)-aryl, wherein arylis as defined above.

The term “heteroaryl” as used herein is intended to include aromatic,heterocyclic ring systems containing one or more heteroatoms selectedfrom nitrogen, oxygen and sulphur such as 5 to 7 membered monocyclic and8 to 14 membered bi- and tricyclic aromatic, heterocyclic ring systemscontaining one or more heteroatoms selected from nitrogen, oxygen andsulphur. Representative examples are furyl, thienyl, pyrrolyl,pyrazolyl, 3-oxopyrazolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl,isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,1,3,5- triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl,thiadiazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl,benzimidazolyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl,benzisoxazolyl, purinyl, quinazolinyl, quinolizinyl, quinolinyl,isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl,azepinyl, diazepinyl, acridinyl, thiazolidinyl, 2-thiooxothiazolidinyland the like. Heteroaryl is also intended to include the partiallyhydrogenated derivatives of the ring systems enumerated above.Non-limiting examples of such partially hydrogenated derivatives are2,3-dihydrobenzofuranyl, pyrrolinyl, pyrazolinyl, indolinyl,oxazolidinyl, oxazolinyl, oxazepinyl and the like.

The term “heteroarylene” as used herein is intended to include divalent,aromatic, heterocyclic ring systems containing one or more heteroatomsselected from nitrogen, oxygen and sulphur such as 5 to 7 memberedmonocyclic and 8 to 14 membered bi- and tricyclic aromatic, heterocyclicring systems containing one or more heteroatoms selected from nitrogen,oxygen and sulphur. Representative examples are furylene, thienylene,pyrrolylene, oxazolylene, thiazolylene, imidazolylene, isoxazolylene,isothiazolylene, 1,2,3-triazolylene, 1,2,4-triazolylene, pyranylene,pyridylene, pyridazinylene, pyrimidinylene, pyrazinylene,1,2,3-triazinylene, 1,2,4-triazinylene, 1,3,5- triazinylene,1,2,3-oxadiazolylene, 1,2,4-oxadiazolylene, 1,2,5-oxadiazolylene,1,3,4-oxadiazolylene, 1,2,3-thiadiazolylene, 1,2,4-thiadiazolylene,1,2,5-thiadiazolylene, 1,3,4-thiadiazolylene, tetrazolylene,thiadiazinylene, indolylene, isoindolylene, benzofurylene,benzothienylene, indazolylene, benzimidazolylene, benzthiazolylene,benzisothiazolylene, benzoxazolylene, benzisoxazolylene, purinylene,quinazolinylene, quinolizinylene, quinolinylene, isoquinolinylene,quinoxalinylene, naphthyridinylene, pteridinylene, carbazolylene,azepinylene, diazepinylene, acridinylene and the like. Heteroaryl isalso intended to include the partially hydrogenated derivatives of thering systems enumerated above. Non-limiting examples of such partiallyhydrogenated derivatives are 2,3-dihydrobenzofuranylene, pyrrolinylene,pyrazolinylene, indolinylene, oxazolidinylene, oxazolinylene,oxazepinylene and the like.

The term “ArG1” as used herein is intended to include an aryl or aryleneradical as applicable, where aryl or arylene are as defined above butlimited to phenyl, biphenylyl, naphthyl, anthracenyl, phenanthrenyl,fluorenyl, indenyl, and azulenyl as well as the corrresponding divalentradicals.

The term “ArG2” as used herein is intended to include an aryl or aryleneradical as applicable, where aryl or arylene are as defined above butlimited to phenyl, biphenylyl, naphthyl, fluorenyl, and indenyl, as wellas the corrresponding divalent radicals.

The term “Het1” as used herein is intended to include a heteroaryl orheteroarylene radical as applicable, where heteroaryl or heteroaryleneare as defined above but limited to furyl, thienyl, pyrrolyl, pyrazolyl,3-oxopyrazolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl,isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3 triazinyl, 1,2,4-triazinyl,1,3,5-triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,54hiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl,thiadiazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl,benzimidazolyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl,benzisoxazolyl, purinyl, quinazolinyl, quinolizinyl, quinolinyl,isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl,azepinyl, diazepinyl, acridinyl, thiazolidinyl, 2-thiooxothiazolidinyl,as well as the corrresponding divalent radicals.

The term “Het2” as used herein is intended to include a heteroaryl orheteroarylene radical as applicable, where heteroaryl or heteroaryleneare as defined above but limited to furyl, thienyl, pyrrolyl, pyrazolyl,3-oxopyrazolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl,isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,1,3,5-triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl,thiadiazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl,benzimidazolyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl,benzisoxazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, carbazolyl,thiazolidinyl, 2-thiooxothiazolidinyl, as well as the corrrespondingdivalent radicals.

The term “Het3” as used herein is intended to include a heteroaryl orheteroarylene radical as applicable, where heteroaryl or heteroaryleneare as defined above but limited to furyl, thienyl, pyrrolyl, pyrazolyl,3-oxopyrazolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl,isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, tetrazolyl,indolyl, isoindolyl, benzofuryl, benzothienyl, benzimidazolyl,benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, quinolyl,isoquinolyl, quinoxalinyl, carbazolyl, thiazolidinyl,2-thiooxothiazolidinyl, as well as the corrresponding divalent radicals.

“Aryl-C₁-C₆-alkyl”, “heteroaryl-C₁-C₆-alkyl”, “aryl-C₂-C₆-alkenyl” etc.is intended to mean C₁-C₆-alkyl or C₂-C₆-alkenyl as defined above,substituted with an aryl or heteroaryl as defined above, for example:

The term “optionally substituted” as used herein means that the groupsin question are either unsubstituted or substituted with one or more ofthe substituents specified. When the groups in question are substitutedwith more than one substituent the substituents may be the same ordifferent.

Certain of the above defined terms may occur more than once in thestructural formulae, and upon such occurrence each term shall be definedindependently of the other.

Furthermore, when using the terms “independently are” and “independentlyselected from” it should be understood that the groups in question maybe the same or different.

The term “substituted with one or more substituents” as used herein isintended to include one to four substituents, such as one to threesubstitents, one to two substituents, or even one substituent.

The term “treatment” as used herein means the management and care of apatient for the purpose of combating a disease, disorder or condition.The term is intended to include the delaying of the progression of thedisease, disorder or condition, the alleviation or relief of symptomsand complications, and/or the cure or elimination of the disease,disorder or condition. The patient to be treated is preferably a mammal,in particular a human being. When in the specification or claims mentionis made of groups of compounds such as benzotriazoles, 3-hydroxy2-napthoic acids, salicylic acids, tetrazoles, thiazolidinediones,5-mercaptotetrazoles, or 4-cyano-1,2,3-triazoles, these groups ofcompounds are intended to include also derivatives of the compounds fromwhich the groups take their name.

The term “insulin” as used herein refers to human insulin as well asderivatives ans analogues hereof as defined below.

The term “human insulin” as used herein refers to insulin naturallyproduced in the human body or recombinantly produced insulin identicalthereto. Recombinant human insulin may be produced in any suitable hostcell, for example the host cells may be bacterial, fungal (includingyeast), insect, animal or plant cells.

The term “insulin derivative” as used herein (and related terms) refersto human insulin or an analogue thereof in which at least one organicsubstituent is bound to one or more of the amino acids.

By the term “analogue of human insulin” as used herein (and relatedterms) is meant human insulin in which one or more amino acids have beendeleted and/or replaced by other amino acids, including non-codeableamino acids, or human insulin comprising additional amino acids, i.e.more than 51 amino acids, such that the resulting analogue possessesinsulin activity.

Rapid acting insulin is intended to mean human insulin, insulinanalogues or insulin derivatives having an onset of action afterinjection or any other form of administration faster or equal to that ofsoluble and neutral formulations of human insulin.

The term “phenolic compound” or similar expressions as used hereinrefers to a compound in which a hydroxyl group is bound directly to abenzene or substituted benzene ring. Examples of such compounds include,but are not limited to, phenol, o-cresol, m-cresol, p-cresol,chloro-cresol, thymol, and 7-hydroxyindole.

DESCRIPTION OF THE INVENTION

The present invention is based on the discovery that the two knownligand binding sites of the R-state insulin hexamer can be used toobtain an insulin composition having improved physical and chemicalstability.

The basic concept underlying the present invention involves reversibleattachment of a ligand to the His^(B10) Zn²⁺ site of the R-statehexamer. The anions currently used in insulin compositions as allostericligands for the R-state hexamers (notably chloride ion) bind only weaklyto the His^(B10) anion site.

The His^(B10) Zn²⁺ site consists of a tunnel or cavity with atriangular-shaped cross-section that extends ˜12 Å from the surface ofthe hexamer down to the His^(B10) Zn²⁺ ion. The diameter of the tunnelvaries along its length and, depending on the nature of the ligandoccupying the site, the opening can be capped over by the Asn^(B3) andPhe^(B1) side chains. The walls of the tunnel are made up of the sidechains of the amino acid residues along one face each of the threealpha-helices. The side chains from each helix that make up the liningof the tunnel are Phe^(B1), Asn^(B3), and Leu^(B6). Therefore, exceptfor the zinc ion, which is coordinated to three His^(B10) residues andis positioned at the bottom of the tunnel, the site is principallyhydrophobic. Depending on the ligand structure, it may be possible forsubstituents on the ligand to make H-bonding interactions with AsnB³ andwith the peptide linkage to Cys^(B7).

In one aspect the invention provides a pharmaceutical compositioncomprising insulin and a zinc-binding ligand which reversibly binds to aHisB10 Zn2+ site of an insulin hexamer, wherein the ligand is selectedfrom the group consisting of benzotriazoles, 3-hydroxy 2-napthoic acids,salicylic acids, tetrazoles, thiazolidinediones, 5-mercaptotetrazoles,or 4-cyano-1,2,3-triazoles, or any enantiomer, diastereomer, including aracemic mixture, tautomer as well as a salt thereof with apharmaceutically acceptable acid or base.

In one embodiment the invention provides a pharmaceutical compositionwherein the zinc-binding ligand is

wherein

-   -   X is ═O, ═S or ═NH    -   Y is —S—, —O— or —NH—    -   R¹ and R⁴ are independently selected from hydrogen or        C₁-C₆-alkyl,    -   R² is hydrogen or C₁-C₆-alkyl or aryl, R¹ and R² may optionally        be combined to form a double bond,    -   R³ and R⁵ are independently selected from hydrogen, halogen,        aryl, C₁-C₆-alkyl, or —C(O)NR¹¹R¹²,    -   A and B are independently selected from C₁-C₆-alkyl, aryl,        aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl or heteroaryl, wherein the        alkyl or alkenyl is optionally substituted with one or more        substituents independently selected from R⁶ and the aryl or        heteroaryl is optionally substituted with up to four        substituents R⁷, R⁸, R⁹, and R¹⁰,    -   A and R³ may be connected through one or two valence bonds, B        and R⁵ may be connected through one or two valence bonds,    -   R⁶ is independently selected from halogen, —CN, —CF₃, —OCF₃,        aryl, —COOH and —NH₂,    -   R⁷, R⁸, R⁹ and R¹⁰ are independently selected from        -   hydrogen, halogen, —CN, —CH₂CN, —CHF₂, —CF₃, —OCF₃, —OCHF₂,            —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —OS(O)₂CF₃, —SCF₃, —NO₂,            —OR¹¹, —NR¹¹R¹², —SR¹¹, —NR¹¹S(O)₂R¹², —S(O)₂NR¹¹R¹²,            —S(O)NR¹¹R¹², —S(O)R¹¹, —S(O)₂R¹¹, —OS(O)₂ R¹¹,            —C(O)NR¹¹R¹², —OC(O)NR¹¹R¹², —NR¹¹C(O)R¹², —CH₂C(O)NR¹¹R¹²,            —OC₁-C₆-alkyl-C(O)NR¹¹R¹², —CH₂OR¹¹, —CH₂OC(O)R¹¹,            —CH₂NR¹¹R¹², —OC(O)R¹¹, —OC₁-C₁₅-alkyl-C(O)OR¹¹,            —OC₁-C₆-alkyl-OR¹¹, —SC₁-C₆-alkyl-C(O)OR¹¹,            —C₂-C₆-alkenyl-C(═O)OR¹¹, —NR¹¹—C(═O)—C₁-C₆-alkyl-C(═O)OR¹¹,            —NR¹¹—C(═O)—C₁-C₆-alkenyl-C(═O)OR¹¹, —C(O)OR¹¹, C(O)R¹¹, or            —C₂-C₆-alkenyl-C(═O)R¹¹, ═O, or            —C₂-C₆-alkenyl-C(═O)-NR¹¹R¹²,        -   C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, each of which            may optionally be substituted with one or more substituents            independently selected from R¹³,        -   aryl, aryloxy, aryloxycarbonyl, aroyl, arylsulfanyl,            aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl,            aroyl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl,            heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl,            heteroaryl-C₂-C₆-alkynyl, or C₃-C₆ cycloalkyl, of which each            cyclic moiety may optionally be substituted with one or more            substituents independently selected from R¹⁴,    -   R¹¹ and R¹² are independently selected from hydrogen, OH,        C₁-C₂₀-alkyl, aryl-C₁-C₆-alkyl or aryl, wherein the alkyl groups        may optionally be substituted with one or more substituents        independently selected from R¹⁵, and the aryl groups may        optionally be substituted one or more substituents independently        selected from R¹⁶; R¹¹ and R¹² when attached to the same        nitrogen atom may form a 3 to 8 membered heterocyclic ring with        the said nitrogen atom, the heterocyclic ring optionally        containing one or two further heteroatoms selected from        nitrogen, oxygen and sulphur, and optionally containing one or        two double bonds,    -   R¹³ is independently selected from halogen, —CN, —CF₃, —OCF₃,        —OR¹¹, —C(O)OR¹¹, —NR¹¹R¹², and —C(O)NR¹¹R¹²,    -   R¹⁴ is independently selected from halogen, —C(O)OR¹¹,        —CH₂C(O)OR¹¹, —CH₂OR¹¹, —CN, —CF₃, —OCF₃, —NO₂, —OR¹¹, —NR¹¹R¹²,        S(O)₂R¹¹, aryl and C₁-C₆-alkyl,    -   R¹⁵ is independently selected from halogen, —CN, —CF₃, —OCF₃,        —OC₁-C₆-alkyl, —C(O)OC₁-C₆-alkyl, —COOH and —NH₂,    -   R¹⁶ is independently selected from halogen, —C(O)OC₁-C₆-alkyl,        —COOH, —CN, —CF₃, —OCF₃, —NO₂, —OH, —OC₁-C₆-alkyl, —NH₂, C(═O)        or C₁-C₆-alkyl, or any enantiomer, diastereomer, including a        racemic mixture, tautomer as well as a salt thereof with a        pharmaceutically acceptable acid or base.

In another embodiment the invention provides a pharmaceuticalcomposition wherein X is ═O or ═S.

In another embodiment the invention provides a pharmaceuticalcomposition wherein X is ═O.

In another embodiment the invention provides a pharmaceuticalcomposition wherein X is ═S.

In another embodiment the invention provides a pharmaceuticalcomposition wherein Y is —O— or —S—.

In another embodiment the invention provides a pharmaceuticalcomposition wherein Y is —O—.

In another embodiment the invention provides a pharmaceuticalcomposition wherein Y is —S—.

In another embodiment the invention provides a pharmaceuticalcomposition wherein A is aryl optionally substituted with up to foursubstituents, R⁷, R⁸, R⁹, and R¹⁰ which may be the same or different.

In another embodiment the invention provides a pharmaceuticalcomposition wherein A is selected from ArG1 optionally substituted withup to four substituents, R⁷, R⁸, R⁹, and R¹⁰ which may be the same ordifferent.

In another embodiment the invention provides a pharmaceuticalcomposition wherein A is phenyl or naphtyl optionally substituted withup to four substituents, R⁷, R⁸, R⁹, and R¹⁰ which may be the same ordifferent.

In another embodiment the invention provides a pharmaceuticalcomposition wherein A is

In another embodiment the invention provides a pharmaceuticalcomposition wherein A is phenyl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein A is heteroaryl optionally substituted with up tofour substituents, R⁷, R⁸, R⁹, and R¹⁰ which may be the same ordifferent.

In another embodiment the invention provides a pharmaceuticalcomposition wherein A is selected from Het1 optionally substituted withup to four substituents, R⁷, R⁸, R⁹, and R¹⁰ which may be the same ordifferent.

In another embodiment the invention provides a pharmaceuticalcomposition wherein A is selected from Het2 optionally substituted withup to four substituents, R⁷, R⁸, R⁹, and R¹⁰ which may be the same ordifferent.

In another embodiment the invention provides a pharmaceuticalcomposition wherein A is selected from Het3 optionally substituted withup to four substituents, R⁷, R⁸, R⁹, and R¹⁰ which may be the same ordifferent.

In another embodiment the invention provides a pharmaceuticalcomposition wherein A is selected from the group consisting of indolyl,benzofuranyl, quinolyl, furyl, thienyl, or pyrrolyl, wherein eachheteroaryl may optionally substituted with up to four substituents, R⁷,R⁸, R⁹, and R¹⁰ which may be the same or different.

In another embodiment the invention provides a pharmaceuticalcomposition wherein A is benzofuranyl optionally substituted with up tofour substituents R⁷, R⁸, R⁹, and R¹⁰ which may be the same ordifferent.

In another embodiment the invention provides a pharmaceuticalcomposition wherein A is

In another embodiment the invention provides a pharmaceuticalcomposition wherein A is carbazolyl optionally substituted with up tofour substituents R⁷, R⁸, R⁹, and R¹⁰ which may be the same ordifferent.

In another embodiment the invention provides a pharmaceuticalcomposition wherein A is

In another embodiment the invention provides a pharmaceuticalcomposition wherein A is quinolyl optionally substituted with up to foursubstituents R⁷, R⁸, R⁹, and R¹⁰ which may be the same or different.

In another embodiment the invention provides a pharmaceuticalcomposition wherein A is

In another embodiment the invention provides a pharmaceuticalcomposition wherein A is indolyl optionally substituted with up to foursubstituents R⁷, R⁸, R⁹, and R¹⁰ which may be the same or different.

In another embodiment the invention provides a pharmaceuticalcomposition wherein A is

In another embodiment the invention provides a pharmaceuticalcomposition wherein R¹ is hydrogen.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R² is hydrogen.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R¹ and R² are combined to form a double bond.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R³ is C₁-C₆-alkyl, halogen, or C(O)NR¹⁶R¹⁷.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R³ is C₁-C₆-alkyl or C(O)NR¹⁶R¹⁷.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R³ is methyl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein B is phenyl optionally substituted with up to foursubstituents, R⁷, R⁸, R⁹, and R¹⁰ which may be the same or different.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁴ is hydrogen.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁵ is hydrogen.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁶ is aryl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁶ is phenyl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁷, R⁸, R⁹ and R¹⁰ are independently selected from

-   -   hydrogen, halogen, —NO₂, —OR¹¹, —NR¹¹R¹², —SR¹¹, —NR¹¹S(O)₂R¹²,        —S(O)₂NR¹¹R¹², —S(O)NR¹¹R¹², —S(O)R¹¹, —S(O)₂R¹¹, —OS(O)₂ R¹¹,        —NR¹¹C(O)R¹², —CH₂OR¹¹, —CH₂OC(O)R¹¹, —CH₂NR¹¹R¹², —OC(O)R¹¹,        —OC₁-C₆-alkyl-C(O)OR¹¹, —OC_(-C) ₆-alkyl-C(O)NR¹¹R¹²,        —OC₁-C₆-alkyl-OR¹¹, —SC₁-C₆-alkyl-C(O)OR¹¹,        —C₂-C₆-alkenyl-C(═O)OR¹¹, —C(O)OR¹¹, or —C₂-C₆-alkenyl-C(═O)R¹¹,    -   C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, which may each        optionally be substituted with one or more substituents        independently selected from R¹³    -   aryl, aryloxy, aroyl, arylsulfanyl, aryl-C₁-C₆-alkoxy,        aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, aroyl-C₂-C₆-alkenyl,        aryl-C₂-C₆-alkynyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, wherein        each of the cyclic moieties optionally may be substituted with        one or more substituents independently selected from R¹⁴

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁷, R⁸, R⁹ and R¹⁰ are independently selected from

-   -   hydrogen, halogen, —NO₂, —OR¹¹, —NR¹¹R¹², —SR¹¹, —S(O)₂R¹¹,        —OS(O)₂ R¹¹, —CH₂OC(O)R¹¹, —OC(O)R¹¹, —OC₁-C₆-alkyl-C(O)OR¹¹,        —OC₁-C₆-alkyl-OR¹¹, —SC₁-C₆-alkyl-C(O)OR¹¹, —C(O)OR¹¹, or        —C₂-C₆-alkenyl-C(═O)R¹¹,    -   C₁-C₆-alkyl or C₁-C₆-alkenyl which may each optionally be        substituted with one or more substituents independently selected        from R¹³    -   aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl,        heteroaryl,    -   of which each of the cyclic moieties optionally may be        substituted with one or more substituents independently selected        from R¹⁴

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁷, R⁸, R⁹ and R¹⁰ are independently selected from

-   -   hydrogen, halogen, —NO₂, —OR¹¹, —NR¹¹R¹², —SR¹¹, —S(O)₂R¹¹,        —OS(O)₂ R¹¹, —CH₂CC(O)R¹¹, —OC(O)R¹¹, —OC₁-C₆-alkyl-C(O)OR¹¹,        —OC₁-C₆-alkyl-OR¹¹, —SC₁-C₆-alkyl-C(O)OR¹¹, —C(O)OR¹¹, or        —C₂-C₆-alkenyl-C(═O)R¹¹,    -   C₁-C₆-alkyl or C₁-C₆— which may each optionally be substituted        with one or more substituents independently selected from R¹³    -   aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl,        heteroaryl,    -   of which each of the cyclic moieties optionally may be        substituted with one or more substituents independently selected        from R¹⁴

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁷, R⁸, R⁹ and R¹⁰ are independently selected from

-   -   hydrogen, halogen, —OR¹¹, —OC₁-C₆-alkyl-C(O)OR¹¹, or —C(O)O^(R)        ¹¹,    -   C₁-C₆-alkyl which may each optionally be substituted with one or        more substituents independently selected from R¹³    -   aryl, aryloxy, aryl-C₁-C₆-alkoxy,    -   of which each of the cyclic moieties optionally may be        substituted with one or more substituents independently selected        from R¹⁴.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁷, R⁸, R⁹ and R¹⁰ are independently selected from

-   -   hydrogen, halogen, —OR¹¹, —OC₁-C₆-alkyl-C(O)OR¹¹, or —C(O)O^(R)        ¹¹,    -   C₁-C₆-alkyl which may optionally be substituted with one or more        substituents independently selected from R¹³    -   phenyl, phenyloxy, phenyl-C₁-C₆-alkoxy, wherein each of the        cyclic moieties optionally may be substituted with one or more        substituents independently selected from R¹⁴.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R¹¹ and R¹² are independently selected fromhydrogen, C₁-C₂₀-alkyl, aryl or aryl-C₁-C₆-alkyl, wherein the alkylgroups may optionally be substituted with one or more substituentsindependently selected from R¹⁵, and the aryl groups may optionally besubstituted one or more substituents independently selected from R¹⁶;R¹¹ and R¹² when attached to the same nitrogen atom may form a 3 to 8membered heterocyclic ring with the said nitrogen atom, the heterocyclicring optionally containing one or two further heteroatoms selected fromnitrogen, oxygen and sulphur, and optionally containing one or twodouble bonds.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R¹¹ and R¹² are independently selected fromhydrogen, C₁-C₂₀-alkyl, aryl or aryl-C₁-C₆-alkyl, wherein the alkylgroups may optionally be substituted with one or more substituentsindependently selected from R¹⁵, and the aryl groups may optionally besubstituted one or more substituents independently selected from R¹⁶.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R¹¹ and R¹² are independently selected from phenylor phenyl-C₁-C₆-alkyl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein one or both of R¹¹ and R¹² are methyl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R¹³ is independently selected from halogen, CF₃,OR¹¹ or NR¹¹R¹².

In another embodiment the invention provides a pharmaceuticalcomposition wherein R¹³ is independently selected from halogen or OR¹¹.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R¹³ is OR¹¹.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R¹⁴ is independently selected from halogen,—C(O)OR¹¹, —CN, —CF₃, —OR¹¹, S(O)₂R¹¹, and C₁-C₆-alkyl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R¹⁴ is independently selected from halogen,—C(O)OR¹¹, or —O^(R) ¹¹.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R¹⁵ is independently selected from halogen, —CN,—CF₃, —C(O)OC₁-C₆-alkyl, and —COOH.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R¹⁵ is independently selected from halogen or—C(O)OC₁-C₆-alkyl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R¹⁶ is independently selected from halogen,—C(O)OC₁-C₆-alkyl, —COOH, —NO₂, —OC₁-C₆-alkyl, —NH₂, C(═O) orC₁-C₆-alkyl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R¹⁶ is independently selected from halogen,—C(O)OC₁-C₆-alkyl, —COOH, —NO₂, or C₁-C₆-alkyl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein the zinc-binding ligand is

wherein

-   -   R¹⁹ is hydrogen or C₁-C₆-alkyl,    -   R²⁰ is hydrogen or C₁-C₆-alkyl,    -   D and F are a valence bond or C₁-C₆-alkylene optionally        substituted with one or more substituents independently selected        from R⁷²,    -   R⁷² is independently selected from hydroxy, C₁-C₆-alkyl, or        aryl,    -   E is C₁-C₆-alkyl, aryl or heteroaryl, wherein the aryl or        heteroaryl is optionally substituted with up to three        substituents R²¹, R²² and R²³,    -   G is C₁-C₆-alkyl, aryl or heteroaryl, wherein the aryl or        heteroaryl is optionally substituted with up to three        substituents R²⁴, R²⁵ and R²⁶,    -   R¹⁷ R¹⁸, R²¹, R²², R²³, R²⁴, R²⁵ and R²⁶ are independently        selected from        -   hydrogen, halogen, —CN, —CH₂CN, —CHF₂, —CF₃, —OCF₃, —OCHF₂,            —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —SCF₃, —NO₂, —OR²⁷,            —NR²⁷R²⁸, —SR²⁷, —NR²⁷S(O)₂R²⁸, —S(O)₂NR²⁷R²⁸, —S(O)NR²⁷R²⁸,            —S(O)R²⁷, —S(O)₂R²⁷, —C(O)NR²⁷R²⁸, —OC(O)NR ²⁷R²⁸,            —NR²⁷C(O)R²⁸, —NR²⁷C(O)OR²⁸, —CH₂C(O)NR²⁷R²⁸,            —OCH₂C(O)NR²⁷R²⁸, —CH₂OR²⁷, —CH₂NR²⁷R²⁸, —OC(O)R²⁷,            —OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷,            —C₂-C₆-alkenyl-C(═O)OR²⁷, —NR²⁷—C(═O)—C₁-C₆-alkyl-C(═O)OR²⁷,            —NR²⁷—C(═O)—C₁-C₆-alkenyl-C(═O)OR²⁷,            —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or            —C(O)OR²⁷,        -   C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl,        -   which may optionally be substituted with one or more            substituents independently selected from R²⁹,        -   aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C₁-C₆-alkoxy,            aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl,            heteroaryl, heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl            or heteroaryl-C₂-C₆-alkynyl,        -   of which the cyclic moieties optionally may be substituted            with one or more substituents selected from R³⁰,    -   R²⁷ and R²⁸ are independently selected from hydrogen,        C₁-C₆-alkyl, aryl-C₁-C₆-alkyl or aryl, or R²⁷ and R²⁸ when        attached to the same nitrogen atom together with the said        nitrogen atom may form a 3 to 8 membered heterocyclic ring        optionally containing one or two further heteroatoms selected        from nitrogen, oxygen and sulphur, and optionally containing one        or two double bonds,    -   R²⁹ is independently selected from halogen, —CN, —CF₃, —OCF₃,        —OR²⁷, and —NR²⁷R²⁸,    -   R³⁰ is independently selected from halogen, —C(O)OR²⁷, —CN,        —CF₃, —OCF₃, —NO₂, —OR²⁷, —NR²⁷R²⁸ and C₁-C₆-alkyl, or any        enantiomer, diastereomer, including a racemic mixture, tautomer        as well as a salt thereof with a pharmaceutically acceptable        acid or base. In another embodiment the invention provides a        pharmaceutical composition wherein D is a valence bond.

In another embodiment the invention provides a pharmaceuticalcomposition wherein D is C₁-C₆-alkylene optionally substituted with oneor more hydroxy, C₁-C₆-alkyl, or aryl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein E is aryl or heteroaryl, wherein the aryl orheteroaryl is optionally substituted with up to three substituentsindependently selected from R²¹, R²² and R²³.

In another embodiment the invention provides a pharmaceuticalcomposition wherein E is aryl optionally substituted with up to threesubstituents independently selected from R²¹, R²² and R²³.

In another embodiment the invention provides a pharmaceuticalcomposition wherein E is selected from ArG1 and optionally substitutedwith up to three substituents independently selected from R²¹, R²² andR²³.

In another embodiment the invention provides a pharmaceuticalcomposition wherein E is phenyl optionally substituted with up to threesubstituents independently selected from R²¹, R²² and R²³.

In another embodiment the invention provides a pharmaceuticalcomposition wherein the zinc-binding ligand is

In another embodiment the invention provides a pharmaceuticalcomposition wherein R²¹, R²² and R²³ are independently selected from

-   -   hydrogen, halogen, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃,        —OCF₂CHF₂, —SCF₃, —NO₂, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —C(O)NR²⁷R²⁸,        —OC(O)NR²⁷R²⁸, —NR²⁷C(O)R²⁸, —NR²⁷C(O)R²⁸, —CH₂C(O)NR²⁷R²⁸,        —OCH₂C(O)NR²⁷R²⁸, —CH₂OR²⁷, —CH₂NR²⁷R²⁸, —OC(O)R²⁷,        —OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷,        —C₂-C₆-alkenyl-C(═O)OR²⁷, —NR²⁷—C(═O)—C₁-C₆-alkyl-C(═O)OR²⁷,        —NR²⁷—C(═O)-C₁-C₆-alkenyl-C(═O)OR²⁷—,        —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or        —C(O)OR²⁷,    -   C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl,    -   which may optionally be substituted with one or more        substituents independently selected from R²⁹    -   aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C₁-C₆-alkoxy,        aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl,        heteroaryl, heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl or        heteroaryl-C₂-C₆-alkynyl,    -   of which the cyclic moieties optionally may be substituted with        one or more substituents selected from R³⁰.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R²¹, R²² and R²³ are independently selected from

-   -   hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸,        —NR²⁷C(O)O²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷,        —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷,        —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or        —C(O)OR²⁷,    -   C₁-C₆-alkyl optionally substituted with one or more substituents        independently selected from R²⁹    -   aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl,        heteroaryl, heteroaryl-C₁-C₆-alkyl,    -   of which the cyclic moieties optionally may be substituted with        one or more substituents selected from R³⁰.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R²¹, R²² and R²³ are independently selected from

-   -   hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸,        —NR²⁷C(O)OR²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷,        —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷,        —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or        —C(O)OR²⁷,    -   methyl, ethyl propyl optionally substituted with one or more        substituents independently selected from R²⁹    -   aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl,        heteroaryl, heteroaryl-C₁-C₆-alkyl    -   of which the cyclic moieties optionally may be substituted with        one or more substituents selected from R³⁰.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R²¹, R²² and R²³ are independently selected from

-   -   hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸,        —NR²⁷C(O)OR²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷,        —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷,        —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or        —C(O)OR²⁷,    -   methyl, ethyl propyl optionally substituted with one or more        substituents independently selected from R²⁹    -   ArG1, ArG1-O—, ArG1-C(O)—, ArG1-C₁-C₆-alkoxy, ArG1-C₁-C₆-alkyl,        Het3, Het3-C₁-C₆-alkyl        of which the cyclic moieties optionally may be substituted with        one or more substituents selected from R³⁰.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R²¹, R²² and R²³ are independently selected from

-   -   hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸,        —NR²⁷C(O)OR²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷,        —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷,        —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or        —C(O)OR²⁷,    -   C₁-C₆-alkyl optionally substituted with one or more substituents        independently selected from R²⁹    -   phenyl, phenyloxy, phenyl-C₁-C₆-alkoxy, phenyl-C₁-C₆-alkyl,        of which the cyclic moieties optionally may be substituted with        one or more substituents selected from R³⁰.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R¹⁹ is hydrogen or methyl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R¹⁹ is hydrogen.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R²⁷ is Hydrogen, C₁-C₆-alkyl or aryl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R²⁷ is hydrogen or C₁-C₆-alkyl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R²⁸ is hydrogen or C₁-C₆-alkyl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein F is a valence bond.

In another embodiment the invention provides a pharmaceuticalcomposition wherein F is C₁-C₆-alkylene optionally substituted with oneor more hydroxy, C₁-C₆-alkyl, or aryl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein G is C₁-C₆-alkyl or aryl, wherein the aryl isoptionally substituted with up to three substituents R²⁴, R²⁵ and R²⁶.

In another embodiment the invention provides a pharmaceuticalcomposition wherein G is C₁-C₆-alkyl or ArG1, wherein the aryl isoptionally substituted with up to three substituents R²⁴, R²⁵ and R²⁶.

In another embodiment the invention provides a pharmaceuticalcomposition wherein G is C₁-C₆-alkyl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein G is phenyl optionally substituted with up to threesubstituents R²⁴, R²⁵ and R²⁶.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R²⁴, R²⁵ and R²⁶ are independently selected from

-   -   hydrogen, halogen, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃,        —OCF₂CHF₂, —SCF₃, —NO₂, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —C(O)NR²⁷R²⁸,        —OC(O)NR²⁷R²⁸, —NR²⁷C(O)R²⁸, —NR²⁷C(O)OR²⁸, —CH₂C(O)NR²⁷R²⁸,        —OCH₂C(O)NR²⁷R²⁸, —CH₂OR²⁷, —CH₂NR²⁷R²⁸, —OC(O)R²⁷,        —OC₁-C₆-alkyl-C(O)R²⁷, —SC₁-C₆-alkyl-C(O)—R²⁷,        —C₂-C₆-alkenyl-C(═O)OR²⁷, —NR²⁷—C(═O)—C₁-C₆-alkyl-C(═O)OR²⁷,        —NR²⁷—C(═O)—C₁-C₆-alkenyl-C(═O)OR²⁷—,        —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷,        —C(O)OR²⁷,    -   C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl,    -   which may optionally be substituted with one or more        substituents independently selected from R²⁹    -   aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C₁-C₆-alkoxy,        aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl,        heteroaryl, heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl or        heteroaryl-C₂-C₆-alkynyl,    -   of which the cyclic moieties optionally may be substituted with        one or more substituents selected from R³⁰.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R²⁴, R²⁵ and R²⁶ are independently selected from

-   -   hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸,        —NR²⁷C(O)OR²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷,        —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷,        —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or        —C(O)OR²⁷,    -   C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl,    -   which may optionally be substituted with one or more        substituents independently selected from R²⁹    -   aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C₁-C₆-alkoxy,        aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl,        heteroaryl, heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl or        heteroaryl-C₂-C₆-alkynyl,    -   of which the cyclic moieties optionally may be substituted with        one or more substituents selected from R³⁰.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R²⁴, R²⁵ and R²⁶ are independently selected from

-   -   hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸,        —NR²⁷C(O)OR²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷,        —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷,        —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or        —C(O)OR²⁷,    -   C₁-C₆-alkyl optionally substituted with one or more substituents        independently selected from R²⁹    -   aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl,        heteroaryl, heteroaryl-C₁-C₆-alkyl,    -   of which the cyclic moieties optionally may be substituted with        one or more substituents selected from R³⁰.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R²¹, R²² and R²³ are independently selected from

-   -   hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸,        —NR²⁷C(O)OR²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷,        —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷,        —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or        —C(O)OR²⁷,    -   methyl, ethyl propyl optionally substituted with one or more        substituents independently selected from R²⁹    -   ArG1, ArG1-O—, ArG1-C(O)—, ArG1-C₁-C₆-alkoxy, ArG1-C₁-C₆-alkyl,        Het3, Het3-C₁-C₆-alkyl        of which the cyclic moieties optionally may be substituted with        one or more substituents selected from R³⁰.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R²¹, R²² and R²³ are independently selected from

-   -   hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸,        —NR²⁷C(O)OR ²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷,        —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷,        —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or        —C(O)OR²⁷,    -   methyl, ethyl propyl optionally substituted with one or more        substituents independently selected from R²⁹    -   ArG1, ArG1-O—, ArG1-C(O)—, ArG1-C₁-C₆-alkoxy, ArG1-C₁-C₆-alkyl,        Het3, Het3-C₁-C₆-alkyl        of which the cyclic moieties optionally may be substituted with        one or more substituents selected from R³⁰.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R²¹, R²² and R²³ are independently selected from

-   -   hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸,        —NR²⁷C(O)R²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷,        —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷,        —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or        —C(O)OR²⁷,    -   methyl, ethyl propyl optionally substituted with one or more        substituents independently selected from R²⁹    -   ArG1, ArG1-O—, ArG1-C₁-C₆-alkoxy, ArG1-C₁-C₆-alkyl,        of which the cyclic moieties optionally may be substituted with        one or more substituents selected from R³⁰.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R²⁰ is hydrogen or methyl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R²⁰ is hydrogen.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R²⁷ is hydrogen, C₁-C₆-alkyl or aryl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R²⁷ is hydrogen or C₁-C₆-alkyl or ArG1.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R²⁷ is hydrogen or C₁-C₆-alkyl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R²⁸ is hydrogen or C₁-C₆-alkyl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R¹⁷ and R¹⁸ are independently selected from

-   -   hydrogen, halogen, —CN, —CF₃, —OCF₃, —NO₂, —OR²⁷, —NR²⁷R²⁸,        —SR²⁷, —S(O)R²⁷, —S(O)R²⁷, —C(O)NR²⁷R²⁸, —CH₂OR²⁷, —OC(O)R²⁷,        —OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷, or —C(O)OR²⁷,    -   C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, optionally        substituted with one or more substituents independently selected        from R²⁹    -   aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl,        heteroaryl, heteroaryl-C₁-C₆-alkyl,    -   of which the cyclic moieties optionally may be substituted with        one or more substituents selected from R³⁰.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R¹⁷ and R¹⁸ are independently selected from

-   -   hydrogen, halogen, —CN, —CF₃, —NO₂, —OR²⁷, —NR²⁷R²⁸, or        —C(O)R²⁷,    -   C₁-C₆-alkyl optionally substituted with one or more substituents        independently selected from R²⁹    -   aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl,        heteroaryl, heteroaryl-C₁-C₆-alkyl,    -   of which the cyclic moieties optionally may be substituted with        one or more substituents selected from R³⁰

In another embodiment the invention provides a pharmaceuticalcomposition wherein R¹⁷ and R¹⁸ are independently selected from

-   -   hydrogen, halogen, —CN, —CF₃, —NO₂, —OR²⁷, —NR²⁷R² , or        —C(O)OR²⁷    -   methyl, ethyl propyl optionally substituted with one or more        substituents independently selected from R²⁹    -   aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl,        heteroaryl, heteroaryl-C₁-C₆-alkyl    -   of which the cyclic moieties optionally may be substituted with        one or more substituents selected from R³⁰.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R¹⁷ and R¹⁸ are independently selected from

-   -   hydrogen, halogen, —CN, —CF₃, —NO₂, —OR²⁷, —NR²⁷R²⁸, or        —C(O)OR²⁷    -   methyl, ethyl propyl optionally substituted with one or more        substituents independently selected from R²⁹    -   ArG1, ArG1-O—, ArG1-C(O)—, ArG1-C₁-C₆-alkoxy, ArG1-C₁-C₆-alkyl,        Het3, Het3-C₁-C₆-alkyl        of which the cyclic moieties optionally may be substituted with        one or more substituents selected from R³⁰.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R¹⁷ and R¹⁸ are independently selected from

-   -   hydrogen, halogen, —CN, —CF₃, —NO₂, —OR²⁷, —NR²⁷R²⁸, or        —C(O)OR²⁷    -   C₁-C₆-alkyl optionally substituted with one or more substituents        independently selected from R²⁹    -   phenyl, phenyloxy, phenyl-C₁-C₆-alkoxy, phenyl-C₁-C₆-alkyl,        of which the cyclic moieties optionally may be substituted with        one or more substituents selected from R³⁰.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R²⁷ is hydrogen or C₁-C₆-alkyl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R²⁷ is hydrogen, methyl or ethyl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R²⁸ is hydrogen or C₁-C₆-alkyl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R²⁸ is hydrogen, methyl or ethyl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁷² is —OH or phenyl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein the zinc-binding ligand is

In another embodiment the invention provides a pharmaceuticalcomposition wherein the zinc-binding ligand is of the form H—I-Jwherein H is

wherein the phenyl, naphthalene or benzocarbazole rings are optionallysubstituted with one or more substituents independently selected fromR³¹

-   -   I is selected from        -   a valence bond,        -   —CH₂N(R³²)— or —SO₂N(R³³)—,            wherein Z¹ is S(O)₂ or CH₂, Z² is —NH—, —O— or —S—, and n is            1 or 2,    -   J is        -   C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, which may each            optionally be substituted with one or more substituents            selected from R³⁴,        -   Aryl, aryloxy, aryl-oxycarbonyl-, aroyl, aryl-C₁-C₆-alkoxy-,            aryl-C₁-C₆-alkyl-, aryl-C₂-C₆-alkenyl-, aryl-C₂-C₆-alkynyl-,            heteroaryl, heteroaryl-C₁-C₆-alkyl-,            heteroaryl-C₂-C₆-alkenyl- or heteroaryl-C₂-C₆-alkynyl-,            wherein the cyclic moieties are optionally substituted with            one or more substituents selected from R³⁷,        -   hydrogen,    -   R³¹ is independently selected from hydrogen, halogen, —CN,        —CH₂CN, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂,        —S(O)₂CF₃, —SCF₃, —NO₂, —OR³⁵, —C(O)R³⁵, —NR³⁵R³⁶, —SR³⁵,        —NR³⁵S(O)₂R³⁶, —S(O)₂NR³⁵R³⁶, —S(O)NR³⁵R³⁶, —S(O)R³⁵, —S(O)₂R³⁵,        —C(O)NR³⁵R³⁶, —OC(O)NR³⁵R³⁶, —NR³⁵C(O)R³⁶, —CH₂C(O)NR³⁵R³⁶,        —OCH₂C(O)NR³⁵R³⁶, —CH₂OR³⁵, —CH₂NR³⁵R³⁶, —OC(O)R³⁵,        —OC₁-C₆-alkyl-C(O)OR³⁵,        —SC₁-C₆-alkyl-C(O)OR³⁵—C₂-C₆-alkenyl-C(═O)OR³⁵,        —NR³⁵—C(═)—C₁-C₆-alkyl-C(═O)OR³⁵,        —NR³⁵—C(═)—C₁-C₆-alkenyl-C(═O)OR³⁵—, C₁-C₆-alkyl, C₁-C₆-alkanoyl        or —C(O)OR³⁵,    -   R³² and R³³ are independently selected from hydrogen,        C₁-C₆-alkyl or C₁-C₆-alkanoyl,    -   R³⁴ is independently selected from halogen, —CN, —CF₃, —OCF₃,        —OR³⁵, and —NR³⁵R³⁶,    -   R³⁵ and R³⁶ are independently selected from hydrogen,        C₁-C₆-alkyl, aryl-C₁-C₆-alkyl or aryl, or R³⁵ and R³⁶ when        attached to the same nitrogen atom together with the said        nitrogen atom may form a 3 to 8 membered heterocyclic ring        optionally containing one or two further heteroatoms selected        from nitrogen, oxygen and sulphur, and optionally containing one        or two double bonds,    -   R³⁷ is independently selected from halogen, —C(O)OR³⁵, —C(O)H,        —CN, —CF₃, —OCF₃, —NO₂, —OR³⁵, —NR³⁵R³⁶, C₁-C₆-alkyl or        C₁-C₆-alkanoyl,    -   or any enantiomer, diastereomer, including a racemic mixture,        tautomer as well as a salt thereof with a pharmaceutically        acceptable acid or base.

In another embodiment the invention provides a pharmaceuticalcomposition wherein the zinc-binding ligand is of the form H—I-J,wherein H is

wherein the phenyl, naphthalene or benzocarbazole rings are optionallysubstituted with one or more substituents independently selected fromR³¹,

-   -   I is selected from        -   a valence bond,        -   —CH₂N(R³²)— or —SO₂N(R³³)—,            wherein Z¹ is S(O)₂ or CH₂, Z² is N, —O— or —S—, and n is 1            or 2,    -   J is        -   C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, which may each            optionally be substituted with one or more substituents            selected from R³⁴,        -   Aryl, aryloxy, aryl-oxycarbonyl-, aroyl, aryl-C₁-C₆-alkoxy-,            aryl-C₁-C₆-alkyl-, aryl-C₂-C₆-alkenyl-, aryl-C₂-C₆-alkynyl-,            heteroaryl, heteroaryl-C₁-C₆-alkyl-,            heteroaryl-C₂-C₆-alkenyl- or heteroaryl-C₂-C₆-alkynyl-,            wherein the cyclic moieties are optionally substituted with            one or more substituents selected from R³⁷,        -   hydrogen,    -   R³¹ is independently selected from hydrogen, halogen, —CN,        —CH₂CN, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂,        —S(O)₂CF₃, —SCF₃, —NO₂, —OR³⁵, —C(O)R³⁵, —NR³⁵R³⁶, —SR³⁵,        —NR³⁵S(O)₂R³⁶, —S(O)₂NR³⁵R³⁶, —S(O)NR³⁵R³⁶, —S(O)R³⁵, —S(O)₂R³⁵,        —C(O)NR³⁵R³⁶, —OC(O)NR³⁵R³⁶, —NR³⁵C(O)R³⁶, —CH₂C(O)NR³⁵R³⁶,        —OCH₂C(O)NR³⁵R³⁶, —CH₂OR³⁵, —CH₂NR³⁵R³⁶, —OC(O)R³⁵,        —OC₁-C₆-alkyl-C(O)OR³⁵,        —SC₁-C₆-alkyl-C(O)OR³⁵—C₂-C₆-alkenyl-C(═O)OR³⁵,        —NR³⁵—C(═O)—C₁-C₆-alkyl-C(═O)OR³⁵,        —NR³⁵—C(═O)-C₁-C₆-alkenyl-C(═O)OR³⁵—, C₁-C₆-alkyl,        C₁-C₆-alkanoyl or —C(O)OR³⁵,    -   R³² and R³³ are independently selected from hydrogen,        C₁-C₆-alkyl or C₁-C₆-alkanoyl,    -   R³⁴ is independently selected from halogen, —CN, —CF₃, —OCF₃,        —OR³⁵, and —NR³⁵R³⁶,    -   R³⁵ and R³⁶ are independently selected from hydrogen,        C₁-C₆-alkyl, aryl-C₁-C₆-alkyl or aryl, or R³⁵ and R³⁶ when        attached to the same nitrogen atom together with the said        nitrogen atom may form a 3 to 8 membered heterocyclic ring        optionally containing one or two further heteroatoms selected        from nitrogen, oxygen and sulphur, and optionally containing one        or two double bonds,    -   R³⁷ is independently selected from halogen, —C(O)OR³⁵, —C(O)H,        —CN, —CF₃, —OCF₃, —NO₂, —OR³⁵, —NR³⁵R³⁶, C₁-C₆-alkyl or        C₁-C₆-alkanoyl,    -   or any enantiomer, diastereomer, including a racemic mixture,        tautomer as well as a salt thereof with a pharmaceutically        acceptable acid or base,

With the proviso that R³¹ and J cannot both be hydrogen.

In another embodiment the invention provides a pharmaceuticalcomposition wherein H is

In another embodiment the invention provides a pharmaceuticalcomposition wherein H is

In another embodiment the invention provides a pharmaceuticalcomposition wherein H is

In another embodiment the invention provides a pharmaceuticalcomposition wherein I is a valence bond, —CH₂N(R³²)—, or —SO₂N(R³³)—.

In another embodiment the invention provides a pharmaceuticalcomposition wherein I is a valence bond.

In another embodiment the invention provides a pharmaceuticalcomposition wherein J is

-   -   hydrogen,    -   C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl,    -   which may optionally be substituted with one or more        substituents selected from halogen, —CN, —CF₃, —OCF₃, —OR³⁵, and        —NR³⁵R³⁶,    -   aryl, or heteroaryl, wherein the cyclic moieties are optionally        substituted with one or more substituents independently selected        from R³⁷.

In another embodiment the invention provides a pharmaceuticalcomposition wherein J is

-   -   hydrogen,    -   aryl or heteroaryl, wherein the cyclic moieties are optionally        substituted with one or more substituents independently selected        from R³⁷.

In another embodiment the invention provides a pharmaceuticalcomposition wherein J is

-   -   hydrogen,    -   ArG1 or Het3, wherein the cyclic moieties are optionally        substituted with one or more substituents independently selected        from R³⁷.

In another embodiment the invention provides a pharmaceuticalcomposition wherein J is

-   -   hydrogen,    -   phenyl or naphthyl optionally substituted with one or more        substituents independently selected from R³¹.

In another embodiment the invention provides a pharmaceuticalcomposition wherein J is hydrogen.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R³² and R³³ are independently selected from hydrogenor C₁-C₆-alkyl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R³⁴ is hydrogen, halogen, —CN, —CF₃, —OCF₃, —SCF₃,—NO₂, —OR³⁵, —C(O)R³⁵, —NR³⁵R³⁶, —SR³⁶, —C(O)NR³⁵R³⁶, —OC(O)NR³⁵R³⁶,—NR³⁵C(O)R³⁶, —OC(O)R³⁵, —OC₁-C₆-alkyl-C(O)OR³⁵, —SC₁-C₆-alkyl-C(O)OR³⁵or -C(O)OR³⁵.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R³⁴ is hydrogen, halogen, —CF₃, —NO₂, —OR³⁵,—NR³⁵R³⁶, —SR³⁵, —NR³⁵C(O)R³⁶, or —C(O)OR³⁵.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R³⁴ is hydrogen, halogen, —CF₃, —NO₂, —OR³⁵,—NR³⁵R³⁶, or —NR³⁵C(O)R³⁶.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R³⁴ is hydrogen, halogen, or —OR³⁵.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R³⁵ and R³⁶ are independently selected fromhydrogen, C₁-C₆-alkyl, or aryl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R³⁵ and R³⁶ are independently selected from hydrogenor C₁-C₆-alkyl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R³⁷ is halogen, —C(O)OR³⁵, —CN, —CF₃, —OR³⁵,—NR³⁵R³⁶, C₁-C₆-alkyl or C₁-C₆-alkanoyl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R³⁷ is halogen, —C(O)OR³⁵, —OR³⁵, —NR³⁵R³⁶,C₁-C₆-alkyl or C₁-C₆-alkanoyl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R³⁷ is halogen, —C(O)OR³⁵ or —OR³⁵.

In another embodiment the invention provides a pharmaceuticalcomposition wherein the zinc-binding ligand is

wherein K is a valence bond, C₁-C₆-alkylene, —NH—C(═O)—U—,—C₁-C₆-alkyl-S—, —C₁-C₆-alkyl-O—, —C(═O)—, or —C(═O)—NH—, wherein anyC₁-C₆-alkyl moiety is optionally substituted with R³⁸,

-   -   U is a valence bond, C₁-C₆-alkenylene, —C₁-C₆-alkyl-O— or        C₁-C₆-alkylene wherein any C₁-C₆-alkyl moiety is optionally        substituted with C₁-C₆-alkyl,    -   R³⁸ is C₁-C₆-alkyl, aryl, wherein the alkyl or aryl moieties are        optionally substituted with one or more substituents        independently selected from R³⁹,    -   R³⁹ is independently selected from halogen, cyano, nitro, amino,    -   M is a valence bond, arylene or heteroarylene, wherein the aryl        or heteroaryl moieties are optionally substituted with one or        more substituents independently selected from R⁴⁰,    -   R⁴⁰ is selected from        -   hydrogen, halogen, —CN, —CH₂CN, —CHF₂, —CF₃, —OCF₃, —OCHF₂,            —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —OS(O)₂CF₃, —SCF₃, —NO₂,            —OR⁴ , —NR⁴¹R⁴², —SR⁴¹, —NR⁴¹S(O)₂R⁴², —S(O)₂NR⁴¹R⁴²,            —S(O)NR⁴¹R⁴², —S(O)R⁴¹, —S(O)₂R⁴¹, —OS(O)₂ R⁴¹,            —C(O)NR⁴¹R⁴², —OC(O)NR⁴¹R⁴², —NR⁴¹C(O)R⁴², —CH₂C(O)NR⁴¹R⁴²,            —OC₁-C₆-alkyl-C(O)NR⁴¹R⁴², —CH₂OR⁴¹, —CH₂OC(O)R⁴¹,            —CH₂NR⁴¹R⁴², —OC(O)R⁴¹, —OC₁-C₆-alkyl-C(O)OR⁴¹,            —OC₁-C₆-alkyl-OR⁴¹, —S—C₁-C₆-alkyl-C(O)OR⁴¹,            —C₂-C₆-alkenyl-C(═O)OR⁴¹, —NR⁴¹-C(═O)—C₁-C₆-alkyl-C(═O)OR⁴¹,            —NR⁴¹—C(═O)—C₁-C₆-alkenyl-C(═O)OR⁴¹, —C(O)OR⁴¹,            —C₂-C₆-alkenyl-C(═O)R⁴¹, ═O, —NH—C(═O)—O—C₁-C₆-alkyl, or            —NH—C(═O)—C(═O)—O—C₁-C₆-alkyl,        -   C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, which may each            optionally be substituted with one or more substituents            selected from R⁴³,        -   aryl, aryloxy, aryloxycarbonyl, aroyl, arylsulfanyl,            aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl,            aroyl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl,            heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl or            heteroaryl-C₂-C₆-alkynyl, wherein the cyclic moieties            optionally may be substituted with one or more substituents            selected from R⁴⁴,    -   R⁴¹ and R⁴² are independently selected from hydrogen, —OH,        C₁-C₆-alkyl, C₁-C₆-alkenyl, aryl-C₁-C₆-alkyl or aryl, wherein        the alkyl moieties may optionally be substituted with one or        more substituents independently selected from R⁴⁵, and the aryl        moieties may optionally be substituted with one or more        substituents independently selected from R⁴⁶; R⁴¹ and R⁴² when        attached to the same nitrogen atom may form a 3 to 8 membered        heterocyclic ring with the said nitrogen atom, the heterocyclic        ring optionally containing one or two further heteroatoms        selected from nitrogen, oxygen and sulphur, and optionally        containing one or two double bonds,    -   R⁴³ is independently selected from halogen, —CN, —CF₃, —OCF₃,        —OR⁴¹, and —NR⁴¹R⁴²    -   R⁴⁴ is independently selected from halogen, —C(O)OR⁴¹,        —CH₂C(O)OR⁴¹, —CH₂OR⁴¹, —CN, —CF₃, —OCF₃, —NO₂, —OR⁴¹, —NR⁴¹R⁴²        and C₁-C₆-alkyl,    -   R⁴⁵ is independently selected from halogen, —CN, —CF₃, —OCF₃,        —O—C₁-C₆-alkyl, —C(O)—O—C₁-C₆-alkyl, —COOH and —NH₂,    -   R⁴⁶ is independently selected from halogen, —C(O)OC₁-C₆-alkyl,        —COOH, —CN, —CF₃, —OCF₃, —NO₂, —OH, —OC₁-C₆-alkyl, —NH₂, C(═O)        or C₁-C₆-alkyl,    -   Q is a valence bond, C₁-C₆-alkylene, —C₁-C₆-alkyl-O—,        —C₁-C₆-alkyl-NH—, —NH—C₁-C₆-alkyl, —NH—C(═O)—, —C(═O)—NH—,        —O—C₁-C₆-alkyl, —C(═O)—, or —C₁-C₆-alkyl-C(═O)—N(R⁴⁷)— wherein        the alkyl moieties are optionally substituted with one or more        substituents independently selected from R⁴⁸,    -   R⁴⁷ and R48 are independently selected from hydrogen,        C₁-C₆-alkyl, aryl optionally substituted with one or more R⁴⁹,    -   R⁴⁹ is independently selected from halogen and —COOH,    -   T is        -   hydrogen,        -   C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,            C₁-C₆-alkyloxy-carbonyl, wherein the alkyl, alkenyl and            alkynyl moieties are optionally substituted with one or more            substituents independently selected from R⁵⁰,        -   aryl, aryloxy, aryloxy-carbonyl, aryl-C₁-C₆-alkyl, aroyl,            aryl-C₁-C₆-alkoxy, aryl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkyny-,            heteroaryl, heteroaryl-C₁-C₆-alkyl,            heteroaryl-C₂-C₆-alkenyl, heteroaryl-C₂-C₆-alkynyl,        -   wherein any alkyl, alkenyl , alkynyl, aryl and heteroaryl            moiety is optionally substituted with one or more            substituents independently selected from R⁵⁰,    -   R⁵⁰ is C₁-C₆-alkyl, C₁-C₆-alkoxy, aryl, aryloxy,        aryl-C₁-C₆-alkoxy, —C(═O)—NH—C₁-C₆-alkyl-aryl, heteroaryl,        heteroaryl-C₁-C₆-alkoxy, —C₁-C₆-alkyl-COOH, —O—C₁-C₆-alkyl-COOH,        —S(O)₂R⁵¹, —C₂-C₆-alkenyl-COOH, —OR⁵¹, —NO₂, halogen, —COOH,        —CF₃, —CN, ═O, —N(R⁵¹R⁵²), wherein the aryl or heteroaryl        moieties are optionally substituted with one or more R⁵³,    -   R⁵¹ and R⁵² are independently selected from hydrogen and        C₁-C₆-alkyl,    -   R⁵³ is independently selected from C₁-C₆-alkyl, C₁-C₆-alkoxy,        —C₁-C₆-alkyl-COOH, —C₂-C₆-alkenyl-COOH, —OR⁵¹, —NO₂, halogen,        —COOH, —CF₃, —CN, or —N(R⁵¹R⁵²),    -   or any enantiomer, diastereomer, including a racemic mixture,        tautomer as well as a salt thereof with a pharmaceutically        acceptable acid or base.

In another embodiment the invention provides a pharmaceuticalcomposition wherein K is a valence bond, C₁-C₆-alkylene, —NH—C(═O)—U—,—C₁-C₆-alkyl-S—, —C₁-C₆-alkyl-O—, or —C(═O)—, wherein any C₁-C₆-alkylmoiety is optionally substituted with R³⁸. l

In another embodiment the invention provides a pharmaceuticalcomposition wherein K is a valence bond, C₁-C₆-alkylene, —NH—C(═O)—U—,—C₁-C₆-alkyl-S—, or —C₁-C₆-alkyl-O, wherein any C₁-C₆-alkyl moiety isoptionally substituted with R³⁸.

In another embodiment the invention provides a pharmaceuticalcomposition wherein K is a valence bond, C₁-C₆-alkylene, or —NH—C(═O)—U,wherein any C₁-C₆-alkyl moiety is optionally substituted with R³⁸.

In another embodiment the invention provides a pharmaceuticalcomposition wherein K is a valence bond or C₁-C₆-alkylene, wherein anyC₁-C₆-alkyl moiety is optionally substituted with R³⁸.

In another embodiment the invention provides a pharmaceuticalcomposition wherein K is a valence bond or —NH—C(═O)—U.

In another embodiment the invention provides a pharmaceuticalcomposition wherein K is a valence bond.

In another embodiment the invention provides a pharmaceuticalcomposition wherein U is a valence bond or —C₁-C₆-alkyl-O—.

In another embodiment the invention provides a pharmaceuticalcomposition wherein U is a valence bond.

In another embodiment the invention provides a pharmaceuticalcomposition wherein M is arylene or heteroarylene, wherein the aryleneor heteroarylene moieties are optionally substituted with one or moresubstituents independently selected from R⁴⁰.

In another embodiment the invention provides a pharmaceuticalcomposition wherein M is ArG1 or Het1, wherein the arylene orheteroarylene moieties are optionally substituted with one or moresubstituents independently selected from R⁴⁰.

In another embodiment the invention provides a pharmaceuticalcomposition wherein M is ArG1 or Het2, wherein the arylene orheteroarylene moieties are optionally substituted with one or moresubstituents independently selected from R⁴⁰.

In another embodiment the invention provides a pharmaceuticalcomposition wherein M is ArG1 or Het3, wherein the arylene orheteroarylene moieties are optionally substituted with one or moresubstituents independently selected from R⁴⁰.

In another embodiment the invention provides a pharmaceuticalcomposition wherein M is phenylene optionally substituted with one ormore substituents independently selected from R⁴⁰.

In another embodiment the invention provides a pharmaceuticalcomposition wherein M is indolylene optionally substituted with one ormore substituents independently selected from R⁴⁰.

In another embodiment the invention provides a pharmaceuticalcomposition wherein M is

In another embodiment the invention provides a pharmaceuticalcomposition wherein M is carbazolylene optionally substituted with oneor more substituents independently selected from R⁴⁰.

In another embodiment the invention provides a pharmaceuticalcomposition wherein M is

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁴⁰ is selected from

-   -   hydrogen, halogen, —CN, —CF₃, —OCF₃, —NO₂, —OR⁴¹, —NR⁴¹R⁴²,        —SR⁴¹, —S(O)₂R⁴¹, —NR⁴¹C(O)R⁴², —OC₁-C₆-alkyl-C(O)NR⁴¹R⁴²,        —C₂-C₆-alkenyl-C(═O)OR⁴¹, —C(O)OR⁴¹, ═O,        —NH—C(═O)—O—C₁-C₆-alkyl, or —NH—C(═O)—C(═O)—O—C₁-C₆-alkyl,    -   C₁-C₆-alkyl or C₂-C₆-alkenyl which may each optionally be        substituted with one or more substituents independently selected        from R⁴³,    -   aryl, aryloxy, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl,        aryl-C₂-C₆-alkenyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, or        heteroaryl-C₂-C₆-alkenyl, wherein the cyclic moieties optionally        may be substituted with one or more substituents selected from        R⁴⁴.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁴⁰ is selected from

-   -   hydrogen, halogen, —CN, —CF₃, —OCF₃, —NO₂, —OR⁴¹, —NR⁴¹R⁴²,        —SR⁴¹, —S(O)₂R⁴¹, —NR⁴¹C(O)R⁴², —OC₁-C₆-alkyl-C(O)NR⁴¹R⁴²,        —C₂-C₆-alkenyl-C(═O)OR⁴¹, —C(O)OR⁴¹, ═O,        —NH—C(═O)—O—C₁-C₆-alkyl, or —NH—C(═O)—C(═O)—O—C₁-C₆-alkyl,    -   C₁-C₆-alkyl or C₂-C₆-alkenyl which may each optionally be        substituted with one or more substituents independently selected        from R⁴³,    -   ArG1, ArG1-O—, ArG1-C₁-C₆-alkoxy, ArG1-C₁-C₆-alkyl,        ArG1-C₂-C₆-alkenyl, Het3, Het3-C₁-C₆-alkyl, or        Het3-C₂-C₆-alkenyl, wherein the cyclic moieties optionally may        be substituted with one or more substituents selected from R⁴⁴.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁴⁰ is selected from

-   -   hydrogen, halogen, —CF₃, —NO₂, —OR⁴¹, —NR⁴¹R⁴², —C(O)OR⁴¹, ═O,        or —NR⁴¹C(O)R⁴²,    -   C₁-C₆-alkyl,    -   ArG1.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁴⁰ is selected from

-   -   Halogen, —NO₂, —OR⁴¹, —NR⁴¹R⁴², —C(O)OR⁴¹, or —NR⁴¹C(O)R⁴²,    -   Methyl,    -   Phenyl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁴¹ and R⁴² are independently selected fromhydrogen, C₁-C₆-alkyl, or aryl, wherein the aryl moieties may optionallybe substituted with halogen or —COOH.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁴¹ and R⁴² are independently selected fromhydrogen, methyl, ethyl, or phenyl, wherein the phenyl moieties mayoptionally be substituted with halogen or —COOH.

In another embodiment the invention provides a pharmaceuticalcomposition wherein Q is a valence bond, C₁-C₆-alkylene,—C₁-C₆-alkyl-O—, —C₁-C₆-alkyl-NH—, —NH-C₁-C₆-alkyl, —NH—C(═O)—,—C(═O)—NH—, —O—C₁-C₆-alkyl, —C(═O)—, or —C₁-C₆-alkyl-C(═O)—N(R⁴⁷)—wherein the alkyl moieties are optionally substituted with one or moresubstituents independently selected from R⁴⁸.

In another embodiment the invention provides a pharmaceuticalcomposition wherein Q is a valence bond, —CH₂—, —CH₂—CH₂—, —CH₂—O—,—CH₂—CH₂—O—, —CH₂—NH—, —CH₂—CH₂—NH—, —NH—CH₂—, —NH—CH₂—CH₂—, —NH—C(═O)—,—C(═O)—NH—, —O—CH₂—, —O—CH₂—CH₂—, or —C(═O)—.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁴⁷ and R⁴⁸ are independently selected fromhydrogen, methyl and phenyl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein T is

-   -   hydrogen,    -   C₁-C₆-alkyl optionally substituted with one or more substituents        independently selected from R⁵⁰,    -   aryl, aryl-C₁-C₆-alkyl, heteroaryl, wherein the alkyl, aryl and        heteroaryl moieties are optionally substituted with one or more        substituents independently selected from R⁵⁰.

In another embodiment the invention provides a pharmaceuticalcomposition wherein T is

-   -   hydrogen,    -   C₁-C₆-alkyl optionally substituted with one or more substituents        independently selected from R⁵⁰,    -   ArG1, ArG1-C₁-C₆-alkyl, Het3, wherein the alkyl, aryl and        heteroaryl moieties are optionally substituted with one or more        substituents independently selected from R⁵⁰.

In another embodiment the invention provides a pharmaceuticalcomposition wherein T is

-   -   hydrogen,    -   C₁-C₆-alkyl, optionally substituted with one or more        substituents independently selected from R⁵⁰,    -   phenyl, phenyl-C₁-C₆-alkyl, wherein the alkyl and phenyl        moieties are optionally substituted with one or more        substituents independently selected from R⁵⁰.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁵⁰ is C₁-C₆-alkyl, C₁-C₆-alkoxy, aryl, aryloxy,aryl-C₁-C₆-alkoxy, —C(═O)—NH—C₁-C₆-alkyl-aryl, heteroaryl,—C₁-C₆-alkyl-COOH, —O—C₁-C₆-alkyl-COOH, —S(O)₂R⁵¹, —C₂-C₆-alkenyl-COOH,—OR⁵¹, —NO₂, halogen, —COOH, —CF₃, —CN, ═O, —N(R⁵¹R⁵²), wherein the arylor heteroaryl moieties are optionally substituted with one or more R⁵³.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁵⁰ is C₁-C₆-alkyl, C₁-C₆-alkoxy, aryl, aryloxy,aryl-C₁-C₆-alkoxy , —OR⁵¹, —NO₂, halogen, —COOH, —CF₃, wherein any arylmoiety is optionally substituted with one or more R⁵³.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁵⁰ is C₁-C₆-alkyl, aryloxy, aryl-C₁-C₆-alkoxy,—OR⁵¹, halogen, —COOH, —CF₃, wherein any aryl moiety is optionallysubstituted with one or more R⁵³.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁵⁰ is C₁-C₆-alkyl, ArG1-O—, ArG1-C₁-C₆-alkoxy,—OR⁵¹, halogen, —COOH, —CF₃, wherein any aryl moiety is optionallysubstituted with one or more R⁵³.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁵⁰ is phenyl, methyl or ethyl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁵⁰ is methyl or ethyl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁵¹ is methyl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁵³ is C₁-C₆-alkyl, C₁-C₆-alkoxy, —OR⁵¹, halogen, or—CF₃.

In another embodiment the invention provides a pharmaceuticalcomposition wherein the zinc-binding ligand is

wherein V is C₁-C₆-alkyl, aryl, heteroaryl, aryl-C₁₋₆-alkyl- oraryl-C₂₋₆-alkenyl-, wherein the alkyl or alkenyl is optionallysubstituted with one or more substituents independently selected fromR⁵⁴, and the aryl or heteroaryl is optionally substituted with one ormore substituents independently selected from R⁵⁵,

-   -   R⁵⁴ is independently selected from halogen, —CN, —CF₃, —OCF₃,        aryl, —COOH and —NH₂,    -   R⁵⁵ is independently selected from        -   hydrogen, halogen, —CN, —CH₂CN, —CHF₂, —CF₃, —OCF₃, —OCHF₂,            —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —OS(O)₂CF₃, —SCF₃, —NO₂,            —OR⁵⁶, —NR⁵⁵R⁵⁷, —SR⁵⁶, —NR⁵⁶S(O)₂R⁵⁷, —S(O)₂NR⁵⁶R⁵⁷,            —S(O)NR⁵⁶R⁵⁷, —S(O)R⁵⁶, —S(O)₂R⁵⁶, —OS(O)₂ R⁵⁶,            —C(O)NR⁵⁶R⁵⁷, —OC(O)NR⁵⁶R⁵⁷, —NR⁵⁶C(O)R⁵⁷, —CH₂C(O)NR⁵⁶R⁵⁷,            —OC₁-C₆-alkyl-C(O)NR⁵⁵R⁵⁷, —CH₂OR⁵⁵, —CH₂OC(O)R⁵⁶,            —CH₂NR⁵⁵R⁵⁷, —OC(O)R⁵⁶, —OC₁-C₈-alkyl-C(O)OR⁵⁶,            —OC₁-C₆-alkyl-OR⁵⁶, —SC₁-C₆-alkyl-C(O)OR⁵⁶,            —C₂-C₆-alkenyl-C(═O)OR⁵⁶, —NR⁵⁶—C(═O)—C₁-C₆-alkyl-C(═O)OR⁵⁶,            —NR⁵⁵—C(═O)—C₁-C₆-alkenyl-C(═O)OR⁵⁶, —C(O)OR⁵⁶, or            C₂-C₆-alkenyl-C(═O)R⁵⁶,        -   C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl,        -   which may optionally be substituted with one or more            substituents selected from R⁵⁸,        -   aryl, aryloxy, aryloxycarbonyl, aroyl, arylsulfanyl,            aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl,            aroyl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl,            heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl or            heteroaryl-C₂-C₆-alkynyl,        -   of which the cyclic moieties optionally may be substituted            with one or more substituents selected from R⁵⁹,    -   R⁵⁶ and R⁵⁷ are independently selected from hydrogen, OH, CF₃,        C₁-C₁₂-alkyl, aryl-C₁-C₆-alkyl, —C(═O)—C₁-C₆-alkyl or aryl,        wherein the alkyl groups may optionally be substituted with one        or more substituents independently selected from R⁶⁰, and the        aryl groups may optionally be substituted with one or more        substituents independently selected from R⁶¹; R⁵⁶ and R⁵⁷ when        attached to the same nitrogen atom may form a 3 to 8 membered        heterocyclic ring with the said nitrogen atom, the heterocyclic        ring optionally containing one or two further heteroatoms        selected from nitrogen, oxygen and sulphur, and optionally        containing one or two double bonds,    -   R⁵⁸ is independently selected from halogen, —CN, —CF₃, —OCF₃,        —OR⁵⁶, and —NR⁵⁶R⁵⁷,    -   R⁵⁹ is independently selected from halogen, —C(O)OR⁵⁶,        —CH₂C(O)OR⁵⁶, —CH₂OR⁵⁶, —CN, —CF₃, —OCF₃, —NO₂, —OR⁵⁶, —NR⁵⁶R⁵⁷        and C₁-C₆-alkyl,    -   R⁶⁰ is independently selected from halogen, —CN, —CF₃, —OCF₃,        —OC₁-C₆-alkyl, —C(O)OC₁-C₆-alkyl, —C(═O)—R⁶², —COOH and —NH₂,    -   R⁶¹ is independently selected from halogen, —C(O)OC₁-C₆-alkyl,        —COOH, —CN, —CF₃, —OCF₃, —NO₂, —OH, —OC₁-C₆-alkyl, —NH₂, C(═O)        or C₁-C₆-alkyl,    -   R⁶² is C₁-C₆-alkyl, aryl optionally substituted with one or more        substituents independently selected from halogen, or heteroaryl        optionally substituted with one or more C₁-C₆-alkyl        independently,    -   or any enantiomer, diastereomer, including a racemic mixture,        tautomer as well as a salt thereof with a pharmaceutically        acceptable acid or base.

In another embodiment the invention provides a pharmaceuticalcomposition wherein V is aryl, heteroaryl, or aryl-C₁₋₆-alkyl-, whereinthe alkyl is optionally substituted with one or more substituentsindependently selected R⁵⁴, and the aryl or heteroaryl is optionallysubstituted with one or more substituents independently selected fromR⁵⁵.

In another embodiment the invention provides a pharmaceuticalcomposition wherein V is aryl, Het1, or aryl-C₁₋₆-alkyl-, wherein thealkyl is optionally substituted with one or more substituentsindependently selected from R⁵⁴, and the aryl or heteroaryl moiety isoptionally substituted with one or more substituents independentlyselected from R⁵⁵.

In another embodiment the invention provides a pharmaceuticalcomposition wherein V is aryl, Het2, or aryl-C₁₋₆-alkyl-, wherein thealkyl is optionally substituted with one or more substituentsindependently selected from R⁵⁴, and the aryl or heteroaryl moiety isoptionally substituted with one or more substituents independentlyselected from R⁵⁵.

In another embodiment the invention provides a pharmaceuticalcomposition wherein V is aryl, Het3, or aryl-C₁₋₆-alkyl-, wherein thealkyl is optionally substituted with one or more substituentsindependently selected from R⁵⁴, and the aryl or heteroaryl moiety isoptionally substituted with one or more substituents independentlyselected from R⁵⁵.

In another embodiment the invention provides a pharmaceuticalcomposition wherein V is aryl optionally substituted with one or moresubstituents independently selected from R⁵⁵.

In another embodiment the invention provides a pharmaceuticalcomposition wherein V is ArG1 optionally substituted with one or moresubstituents independently selected from R⁵⁵.

In another embodiment the invention provides a pharmaceuticalcomposition wherein V is phenyl, naphthyl or anthranyl optionallysubstituted with one or more substituents independently selected fromR⁵⁵.

In another embodiment the invention provides a pharmaceuticalcomposition wherein V is phenyl optionally substituted with one or moresubstituents independently selected from R⁵⁵.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁵⁵ is independently selected from

-   -   halogen, C₁-C₆-alkyl, —CN, —OCF₃, —CF₃, —NO₂, —OR⁵⁶, —NR⁵⁶R⁵⁷,        —NR⁵⁶C(O)R⁵⁷ —SR⁵⁶, —OC₁-C₈-alkyl-C(O)OR⁵⁶, or —C(O)OR⁵⁶,    -   C₁-C₆-alkyl optionally substituted with one or more substituents        independently selected from R⁵⁸    -   aryl, aryl-C₁-C₆-alkyl, heteroaryl, or heteroaryl-C₁-C₆-alkyl    -   of which the cyclic moieties optionally may be substituted with        one or more substituents independently selected from R⁵⁹.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁵⁵ is independently selected from

-   -   halogen, C₁-C₆-alkyl, —CN, —OCF₃, —CF₃, —NO₂, —OR⁵⁶, —NR⁵⁶R⁵⁷,        —NR⁵⁶C(O)R⁵⁷ —SR⁵⁶, —OC₁-C₈-alkyl-C(O)OR⁵⁶, or −C(O)OR⁵⁶    -   C₁-C₆-alkyl optionally substituted with one or more substituents        independently selected from R⁵⁸    -   ArG1, ArG1-C₁-C₆-alkyl, Het3, or Het3-C₁-C₆-alkyl    -   of which the cyclic moieties optionally may be substituted with        one or more substituents independently selected from R⁵⁹.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁵⁵ is independently selected from halogen, —OR⁵⁶,—NR⁵⁶R⁵⁷, —C(O)OR⁵⁶, —OC₁-C₈-alkyl-C(O)OR⁵⁶, —NR⁵⁶C(O)R⁵⁷ orC₁-C₆-alkyl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁵⁵ is independently selected from halogen, —OR⁵⁶,—NR⁵⁶R⁵⁷, —C(O)OR⁵⁶, —OC₁-C₈-alkyl-C(O)OR⁵⁶, —NR⁵⁶C(O)R⁵⁷, methyl orethyl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁵⁶ and R⁵⁷ are independently selected fromhydrogen, CF₃, C₁-C₁₂-alkyl, or —C(═O)—C₁-C₆-alkyl; R⁵⁶ and R⁵⁷ whenattached to the same nitrogen atom may form a 3 to 8 memberedheterocyclic ring with the said nitrogen atom.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁵⁶ and R⁵⁷ are independently selected from hydrogenor C₁-C₁₂-alkyl, R⁵⁶ and R⁵⁷ when attached to the same nitrogen atom mayform a 3 to 8 membered heterocyclic ring with the said nitrogen atom.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁵⁶ and R⁵⁷ are independently selected from hydrogenor methyl, ethyl, propyl butyl, R⁵⁶ and R⁵⁷ when attached to the samenitrogen atom may form a 3 to 8 membered heterocyclic ring with the saidnitrogen atom.

In another embodiment the invention provides a pharmaceuticalcomposition 1 wherein the zinc-binding ligand is

wherein AA is C₁-C₆-alkyl, aryl, heteroaryl, aryl-C₁₋₆-alkyl- oraryl-C₂₋₄-alkenyl-, wherein the alkyl or alkenyl is optionallysubstituted with one or more substituents independently selected fromR⁶³, and the aryl or heteroaryl is optionally substituted with one ormore substituents independently selected from R⁶⁴,

-   -   R⁶³ is independently selected from halogen, —CN, —CF₃, —OCF₃,        aryl, —COOH and —NH₂,    -   R⁶⁴ is independently selected from        -   hydrogen, halogen, —CN, —CH₂CN, —CHF₂, —CF₃, —OCF₃, —OCHF₂,            —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —OS(O)₂CF₃, —SCF₃, —NO₂,            —OR⁶⁵, —NR⁶⁵R⁶⁶, —SR⁶⁵, —NR⁶⁵S(O)₂R⁶⁶, —S(O)₂NR⁶⁵R⁶⁶,            —S(O)NR⁶⁵R⁶⁶, —S(O)R⁶⁵, —S(O)₂R⁶⁵, —C(O)NR⁶⁵R⁶⁶,            —OC(O)NR⁶⁵R⁶⁶, —NR⁶⁵C(O)R⁶⁶, —CH₂C(O)NR⁶⁵R⁶⁶,            —OC₁-C₆-alkyl-C(O)NR⁶⁵R⁶⁶, —CH₂OR⁶⁵, —CH₂OC(O)R⁶⁵,            —CH₂NR⁶⁵R⁶⁶, —OC(O)R⁶⁵, —OC₁-C₆-alkyl-C(O)OR⁶⁵, —OC,            —C₆-alkyl-OR⁶⁵, —SC₁-C₆-alkyl-C(O)OR⁶⁵,            —C₂-C₆-alkenyl-C(═O)OR⁶⁵, —NR⁶⁵—C(═O)—C₁-C₆-alkyl-C(═O)OR⁶⁵,            —NR⁶⁵—C(═O)—C₁-C₆-alkenyl-C(═O)OR⁶⁵, —C(O)OR⁶⁵, or            —C₂-C₆-alkenyl-C(═O)R⁶⁵,        -   C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, each of which            may optionally be substituted with one or more substituents            selected from R⁶⁷,        -   aryl, aryloxy, aryloxycarbonyl, aroyl, arylsulfanyl,            aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl,            aroyl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl,            heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl or            heteroaryl-C₂-C₆-alkynyl,        -   of which the cyclic moieties optionally may be substituted            with one or more substituents selected from R⁶⁸,    -   R⁶⁵ and R⁶⁶ are independently selected from hydrogen, OH, CF₃,        C₁-C₁₂-alkyl, aryl-C₁-C₆-alkyl, —C(═O)—R⁶⁹, aryl or heteroaryl,        wherein the alkyl groups may optionally be substituted with one        or more substituents selected from R⁷⁰, and the aryl and        heteroaryl groups may optionally be substituted with one or more        substituents independently selected from R⁷¹; R⁶⁵ and R⁶⁶ when        attached to the same nitrogen atom may form a 3 to 8 membered        heterocyclic ring with the said nitrogen atom, the heterocyclic        ring optionally containing one or two further heteroatoms        selected from nitrogen, oxygen and sulphur, and optionally        containing one or two double bonds,    -   R⁶⁷ is independently selected from halogen, —CN, —CF₃, —OCF₃,        —OR⁶⁵, and —NR⁶⁵R⁶⁶,    -   R⁶⁸ is independently selected from halogen, —C(O)OR⁶⁵,        —CH₂C(O)OR⁶⁵, —CH₂OR⁶⁵, —CN, —CF₃, —OCF₃, —NO₂, —OR⁶⁵, —NR⁶⁵R⁶⁶        and C₁-C₆-alkyl,    -   R⁶⁹ is independently selected from C₁-C₆-alkyl, aryl optionally        substituted with one or more halogen, or heteroaryl optionally        substituted with one or more C₁-C₆-alkyl,    -   R⁷⁰ is independently selected from halogen, —CN, —CF₃, —OCF₃,        —OC₁-C₆-alkyl, —C(O)OC₁-C₆-alkyl, —COOH and —NH₂,    -   R⁷¹ is independently selected from halogen, —C(O)OC₁-C₆-alkyl,        —COOH, —CN, —CF₃, —OCF₃, —NO₂, —OH, —OC₁-C₆-alkyl, —NH₂, C(═O)        or C₁-C₆-alkyl,    -   or any enantiomer, diastereomer, including a racemic mixture,        tautomer as well as a salt thereof with a pharmaceutically        acceptable acid or base.

In another embodiment the invention provides a pharmaceuticalcomposition wherein AA is aryl, heteroaryl or aryl-C₁₋₆-alkyl-, whereinthe alkyl is optionally substituted with one or more R⁶³, and the arylor heteroaryl is optionally substituted with one or more substituentsindependently selected from R⁶⁴.

In another embodiment the invention provides a pharmaceuticalcomposition wherein AA is aryl or heteroaryl optionally substituted withone or more substituents independently selected from R⁶⁴.

In another embodiment the invention provides a pharmaceuticalcomposition wherein AA is ArG1 or Het1 optionally substituted with oneor more substituents independently selected from R⁶⁴.

In another embodiment the invention provides a pharmaceuticalcomposition wherein AA is ArGl or Het2 optionally substituted with oneor more substituents independently selected from R⁶⁴.

In another embodiment the invention provides a pharmaceuticalcomposition wherein AA is ArG1 or Het3 optionally substituted with oneor more substituents independently selected from R⁶⁴.

In another embodiment the invention provides a pharmaceuticalcomposition wherein AA is phenyl, naphtyl, anthryl, carbazolyl, thienyl,pyridyl, or benzodioxyl optionally substituted with one or moresubstituents independently selected from R⁶⁴.

In another embodiment the invention provides a pharmaceuticalcomposition wherein AA is phenyl or naphtyl optionally substituted withone or more substituents independently selected from R⁶⁴.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁶⁴ is independently selected from hydrogen,halogen, —CF₃, —OCF₃, —OR⁶⁵, —NR⁶⁵R⁶⁶, C₁-C₆-alkyl —OC(O)R⁶⁵,—OC₁-C₆-alkyl-C(O)OR⁶⁵, aryl-C₂-C₆-alkenyl, aryloxy or aryl, whereinC₁-C₆-alkyl is optionally substituted with one or more substituentsindependently selected from R⁶⁷, and the cyclic moieties optionally aresubstituted with one or more substituents independently selected fromR⁶³.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁶⁴ is independently selected from halogen, —CF₃,—OCF₃, —OR⁶⁵, —NR⁶⁵R⁶⁶, methyl, ethyl, propyl, —OC(O)R⁶⁵,—OCH₂—C(O)OR⁶⁵, —OCH₂—CH₂—C(O)OR⁶⁵, phenoxy optionally substituted withone or more substituents independently selected from R⁶⁸.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁶⁵ and R⁶⁶ are independently selected fromhydrogen, CF₃, C₁-C₁₂-alkyl, aryl, or heteroaryl optionally substitutedwith one or more substituents independently selected from R⁷¹.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁶⁵ and R⁶⁶ are independently hydrogen,C₁-C₁₂-alkyl, aryl, or heteroaryl optionally substituted with one ormore substituents independently selected from R⁷¹.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁶⁵ and R⁶⁶ are independently hydrogen, methyl,ethyl, propyl, butyl, 2,2-dimethyl-propyl, ArG1 or Het1 optionallysubstituted with one or more substituents independently selected fromR⁷¹.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁶⁵ and R⁶⁶ are independently hydrogen, methyl,ethyl, propyl, butyl, 2,2-dimethyl-propyl, ArG1 or Het2 optionallysubstituted with one or more substituents independently selected fromR⁷¹.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁶⁵ and R⁶⁶ are independently hydrogen, methyl,ethyl, propyl, butyl, 2,2-dimethyl-propyl, ArG1 or Het3 optionallysubstituted with one or more substituents independently selected fromR⁷¹.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁶⁵ and R⁶⁶ are independently hydrogen, methyl,ethyl, propyl, butyl, 2,2-dimethyl-propyl, phenyl, naphtyl, thiadiazolyloptionally substituted with one or more R⁷¹ independently; or isoxazolyloptionally substituted with one or more substituents independentlyselected from R⁷¹.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁷¹ is halogen or C₁-C₆-alkyl.

In another embodiment the invention provides a pharmaceuticalcomposition wherein R⁷¹ is halogen or methyl.

In another aspect the invention provides a pharmaceutical compositioncomprising insulin and a zinc-binding ligand which reversibly binds to aHis^(B10) Zn²⁺ site of an insulin hexamer, wherein the ligand isselected from the group consisting of benzotriazoles, 3-hydroxy2-napthoic acids, salicylic acids, tetrazoles, thiazolidinediones,5-mercaptotetrazoles, or 4-cyano-1,2,3-triazoles, or any enantiomer,diastereomer, including a racemic mixture, tautomer as well as a saltthereof with a pharmaceutically acceptable acid or base.

In one embodiment hereof the zinc-binding ligand is

wherein

-   -   X is ═O, ═S or ═NH    -   Y is —S—, —O— or —NH—    -   R¹, R^(1A) and R⁴ are independently selected from hydrogen or        C₁-C₆-alkyl,    -   R² and R^(2A) are hydrogen or C₁-C₆-alkyl or aryl, R¹ and R² may        optionally be combined to form a double bond, R^(1A) and R^(2A)        may optionally be combined to form a double bond,    -   R³, R^(3A) and R⁵ are independently selected from hydrogen,        halogen, aryl optionally substituted with one or more        substituents independently selected from R¹⁶, C₁-C₆-alkyl, or        —C(O)NR¹¹R¹²,    -   A, A¹ and B are independently selected from C₁-C₆-alkyl, aryl,        aryl-C₁-C₆-alkyl, —NR¹¹-aryl, aryl-C₂-C₆-alkenyl or heteroaryl,        wherein the alkyl or alkenyl is optionally substituted with one        or more substituents independently selected from R⁶ and the aryl        or heteroaryl is optionally substituted with up to four        substituents R⁷, R⁸, R⁹, and R¹⁰,    -   A and R³ may be connected through one or two valence bonds, B        and R⁵ may be connected through one or two valence bonds,    -   R⁶ is independently selected from halogen, —CN, —CF₃, —OCF₃,        aryl, —COOH and —NH₂,    -   R⁷, R⁸, R⁹ and R¹⁰ are independently selected from        -   hydrogen, halogen, —CN, —CH₂CN, —CHF₂, —CF₃, —OCF₃, —OCHF₂,            —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —OS(O)₂CF₃, —SCF₃, —NO₂,            —OR¹¹, —NR¹¹R¹², —SR¹¹, —NR¹¹S(O)₂R¹², —S(O)₂NR¹¹R¹²,            —S(O)NR¹¹R¹², —S(O)R¹¹, —S(O)₂R¹¹, —OS(O)₂ R¹¹,            —C(O)NR¹¹R¹², —OC(O)NR¹¹R¹², —NR¹¹C(O)R¹², —CH₂C(O)NR¹¹R¹² ,            —OC₁-C₆-alkyl-C(O)NR¹¹R¹², —CH₂OR¹¹, —CH₂OC(O)R¹¹,            —CH₂NR¹¹R¹², —OC(O)R¹¹, —OC₁-C₁₅-alkyl-C(O)OR¹¹,            —OC₁-C₆-alkyl-OR¹¹, —SC₁-C₆-alkyl-C(O)OR¹¹            —C₂-C₆-alkenyl-C(═O)OR¹¹, —NR¹¹—C(═O)—C₁-C₆-alkyl-C(═O)OR¹¹,            —NR¹¹—C(═O)-C₁-C₆-alkenyl-C(═O)OR¹¹, —C(O)OR¹¹, C(O)R¹¹, or            —C₂-C₆-alkenyl-C(═O)R¹¹, ═O, or            —C₂-C₆-alkenyl-C(═O)—NR¹¹R¹²,        -   C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, each of which            may optionally be substituted with one or more substituents            independently selected from R¹³,        -   aryl, aryloxy, aryloxycarbonyl, aroyl, arylsulfanyl,            aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl,            aroyl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl,            heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl,            heteroaryl-C₂-C₆-alkynyl, or C₃-C₆ cycloalkyl,        -   of which each cyclic moiety may optionally be substituted            with one or more substituents independently selected from            R¹⁴,    -   R¹¹ and R¹² are independently selected from hydrogen, OH,        C₁-C₂₀-alkyl, aryl-C₁-C₆-alkyl or aryl, wherein the alkyl groups        may optionally be substituted with one or more substituents        independently selected from R¹⁵, and the aryl groups may        optionally be substituted one or more substituents independently        selected from R¹⁶; R¹¹ and R¹² when attached to the same        nitrogen atom may form a 3 to 8 membered heterocyclic ring with        the said nitrogen atom, the heterocyclic ring optionally        containing one or two further heteroatoms selected from        nitrogen, oxygen and sulphur, and optionally containing one or        two double bonds,    -   R¹³ is independently selected from halogen, —CN, —CF₃, —OCF₃,        —OR¹¹, —C(O)OR¹¹, —NR¹¹R¹², and —C(O)NR¹¹R¹²,    -   R¹⁴ is independently selected from halogen, —C(O)OR¹¹,        —CH₂C(O)OR¹¹, —CH₂OR¹¹, —CN, —CF₃, —OCF₃, —NO₂, —OR¹¹, —NR¹¹R¹²,        —NR¹¹C(O)R¹¹, —S(O)₂R¹¹, aryl and C₁-C₆-alkyl,    -   R¹⁵ is independently selected from halogen, —CN, —CF₃, ═O,        —OCF₃, —OC₁-C₆-alkyl, —C(O)OC₁-C₆-alkyl, —COOH and —NH₂,    -   R¹⁶ is independently selected from halogen, —C(O)OC₁-C₆-alkyl,        —COOH, —CN, —CF₃, —OCF₃, —NO₂, —OH, —OC₁-C₆-alkyl, —NH₂, C(═O)        or C₁-C₆-alkyl, or any enantiomer, diastereomer, including a        racemic mixture, tautomer as well as a salt thereof with a        pharmaceutically acceptable acid or base.

In another embodiment hereof X is ═O or ═S.

In another embodiment hereof X is ═O.

In another embodiment hereof X is ═S.

In another embodiment hereof Y is —O— or —S—.

In another embodiment hereof Y is —O—.

In another embodiment hereof Y is —NH—.

In another embodiment hereof Y is —S—.

In another embodiment hereof A is aryl optionally substituted with up tofour substituents, R⁷, R⁸, R⁹, and R¹⁰ which may be the same ordifferent.

In another embodiment hereof A is selected from ArG1 optionallysubstituted with up to four substituents, R⁷, R⁸, R⁹, and R¹⁰ which maybe the same or different.

In another embodiment hereof A is phenyl or naphtyl optionallysubstituted with up to four substituents, R⁷, R⁸, R⁹, and R¹⁰ which maybe the same or different.

In another embodiment hereof A is

In another embodiment hereof A is phenyl.

In another embodiment hereof A is heteroaryl optionally substituted withup to four substituents, R⁷, R⁸, R⁹, and R¹⁰ which may be the same ordifferent.

In another embodiment hereof A is selected from Het1 optionallysubstituted with up to four substituents, R⁷, R⁸, R⁹, and R¹⁰ which maybe the same or different.

In another embodiment hereof A is selected from Het2 optionallysubstituted with up to four substituents, R⁷, R⁸, R⁹, and R¹⁰ which maybe the same or different.

In another embodiment hereof A is selected from Het3 optionallysubstituted with up to four substituents, R⁷, R⁸, R⁹, and R¹⁰ which maybe the same or different.

In another embodiment hereof A is selected from the group consisting ofindolyl, benzofuranyl, quinolyl, furyl, thienyl, or pyrrolyl, whereineach heteroaryl may optionally substituted with up to four substituents,R⁷, R⁸, R⁹, and R¹⁰ which may be the same or different.

In another embodiment hereof A is benzofuranyl optionally substitutedwith up to four substituents R⁷, R⁸, R⁹, and R¹⁰ which may be the sameor different.

In another embodiment hereof A is

In another embodiment hereof A is carbazolyl optionally substituted withup to four substituents R⁷, R⁸, R⁹, and R¹⁰ which may be the same ordifferent.

In another embodiment hereof A is

In another embodiment hereof A is quinolyl optionally substituted withup to four substituents R⁷, R⁸, R⁹, and R¹⁰ which may be the same ordifferent.

In another embodiment hereof A is

In another embodiment hereof A is indolyl optionally substituted with upto four substituents R⁷, R⁸, R⁹, and R¹⁰ which may be the same ordifferent.

In another embodiment hereof A is

In another embodiment hereof R¹ is hydrogen.

In another embodiment hereof R² is hydrogen.

In another embodiment hereof R¹ and R² are combined to form a doublebond.

In another embodiment hereof R³ is C₁-C₆-alkyl, halogen, or C(O)NR¹⁶R¹⁷.

In another embodiment hereof R³ is C₁-C₆-alkyl or C(O)NR¹⁶R¹⁷.

In another embodiment hereof R³ is methyl.

In another embodiment hereof B is phenyl optionally substituted with upto four substituents, R⁷, R⁸, R⁹, and R¹⁰ which may be the same ordifferent.

In another embodiment hereof R⁴ is hydrogen.

In another embodiment hereof R⁵ is hydrogen.

In another embodiment hereof R⁶ is aryl.

In another embodiment hereof R⁶ is phenyl.

In another embodiment hereof R⁷, R⁸, R⁹ and R¹⁰ are independentlyselected from

-   -   hydrogen, halogen, —NO₂, —OR¹¹, —NR¹¹R¹², —SRR¹¹, —NR¹¹S(O)₂R¹²,        —S(O)₂NR¹¹R¹², —S(O)NR¹¹R¹², —S(O)R¹¹, —S(O)₂R¹¹, —OS(O)₂R¹¹,        —NR¹¹C(O)R¹², —CH₂OR¹¹, —CH₂OC(O)R¹¹, —CH₂NR¹¹R¹², —OC(O)R¹¹,        —OC₁-C₆-alkyl-C(O)OR¹¹, —OC₁-C₆-alkyl-C(O)NR¹¹R¹²,        —OC₁-C₆-alkyl-OR¹¹, —SC₁-C₆-alkyl-C(O)OR¹¹,        —C₂-C₆-alkenyl-C(═O)OR¹¹, —C(O)OR¹¹, or —C₂-C₆-alkenyl-C(═O)R¹¹,    -   C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, which may each        optionally be substituted with one or more substituents        independently selected from R¹³    -   aryl, aryloxy, aroyl, arylsulfanyl, aryl-C₁-C₆-alkoxy,        aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, aroyl-C₂-C₆-alkenyl,        aryl-C₂-C₆-alkynyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, wherein        each of the cyclic moieties optionally may be substituted with        one or more substituents independently selected from R¹⁴

In another embodiment hereof R⁷, R⁸, R⁹ and R¹⁰ are independentlyselected from

-   -   hydrogen, halogen, —NO₂, —OR¹¹, —NR¹¹R¹², —SR¹¹, —S(O)₂R¹¹,        —OS(O)₂ R¹¹, —CH₂OC(O)R¹¹, —OC(O)R¹¹, —OC₁-C₆-alkyl-C(O)OR¹¹,        —OC₁-C₆-alkyl-OR¹¹, —SC₁-C₆-alkyl-C(O)OR¹¹, —C(O)OR¹¹, or        —C₂-C₆-alkenyl-C(═O)R¹¹,    -   C₁-C₆-alkyl or C₁-C₆-alkenyl which may each optionally be        substituted with one or more substituents independently selected        from R¹³    -   aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl,        heteroaryl,    -   of which each of the cyclic moieties optionally may be        substituted with one or more substituents independently selected        from R¹⁴

In another embodiment hereof R⁷, R⁸, R⁹ and R¹⁰ are independentlyselected from

-   -   hydrogen, halogen, —NO₂, —OR¹¹, —NR¹¹R¹², —SR¹¹, —S(O)₂R¹¹,        —OS(O)₂ R¹¹, —CH₂OC(O)R¹¹, —OC(O)R¹¹, —OC₁-C₆-alkyl-C(O)OR¹¹,        —OC₁-C₆-alkyl-OR¹¹, —SC₁-C₆-alkyl-C(O)OR¹¹, —C(O)OR¹¹, or        —C₂-C₆-alkenyl-C(═O)R¹¹,    -   C₁-C₆-alkyl or C₁-C₆—which may each optionally be substituted        with one or more substituents independently selected from R¹³    -   aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl,        heteroaryl,    -   of which each of the cyclic moieties optionally may be        substituted with one or more substituents independently selected        from R¹⁴.

In another embodiment hereof R⁷, R⁸, R⁹ and R¹⁰ are independentlyselected from

-   -   hydrogen, halogen, —OR¹¹, —OC₁-C₆-alkyl-C(O)OR¹¹, or —C(O)OR¹¹,    -   C₁-C₆-alkyl which may each optionally be substituted with one or        more substituents independently selected from R¹³    -   aryl, aryloxy, a ryl-C₁ -C₆-alkoxy,    -   of which each of the cyclic moieties optionally may be        substituted with one or more substituents independently selected        from R¹⁴.

In another embodiment hereof R⁷, R⁸, R⁹ and R¹⁰ are independentlyselected from

-   -   hydrogen, halogen, —OR¹¹, —OC₁-C₆-alkyl-C(O)OR¹¹, or —C(O)OR¹¹,    -   C₁-C₆-alkyl which may each optionally be substituted with one or        more substituents independently selected from R¹³    -   ArG1, ArG1oxy, ArG1-C₁-C₆-alkoxy,        of which each of the cyclic moieties optionally may be        substituted with one or more substituents independently selected        from R¹⁴.

In another embodiment hereof R⁷, R⁸, R⁹ and R¹⁰ are independentlyselected from

-   -   hydrogen, halogen, —OR¹¹, —OC₁-C₆-alkyl-C(O)OR¹¹, or —C(O)OR¹¹,    -   C₁-C₆-alkyl which may optionally be substituted with one or more        substituents independently selected from R¹³    -   phenyl, phenyloxy, phenyl-C₁-C₆-alkoxy, wherein each of the        cyclic moieties optionally may be substituted with one or more        substituents independently selected from R¹⁴.

In another embodiment hereof R¹¹ and R¹² are independently selected fromhydrogen, C₁-C₂₀-alkyl, aryl or aryl-C₁-C₆-alkyl, wherein the alkylgroups may optionally be substituted with one or more substituentsindependently selected from R¹⁵, and the aryl groups may optionally besubstituted one or more substituents independently selected from R¹⁶;R¹¹ and R¹² when attached to the same nitrogen atom may form a 3 to 8membered heterocyclic ring with the said nitrogen atom, the heterocyclicring optionally containing one or two further heteroatoms selected fromnitrogen, oxygen and sulphur, and optionally containing one or twodouble bonds.

In another embodiment hereof R¹¹ and R¹² are independently selected fromhydrogen, C₁-C₂₀-alkyl, aryl or aryl-C₁-C₆-alkyl, wherein the alkylgroups may optionally be substituted with one or more substituentsindependently selected from R¹⁵, and the aryl groups may optionally besubstituted one or more substituents independently selected from R¹⁶.

In another embodiment hereof R¹¹ and R¹² are independently selected fromphenyl or phenyl-C₁-C₆-alkyl.

In another embodiment hereof one or both of R¹¹ and R¹² are methyl.

In another embodiment hereof R¹³ is independently selected from halogen,CF₃, OR¹¹ or NR¹¹R².

In another embodiment hereof R¹³ is independently selected from halogenor OR¹¹.

In another embodiment hereof R¹³ is OR¹¹.

In another embodiment hereof R¹⁴ is independently selected from halogen,—C(O)OR¹¹, —CN, —CF₃, —OR¹¹, S(O)₂R¹¹, and C₁-C₆-alkyl.

In another embodiment hereof R¹⁴ is independently selected from halogen,—C(O)OR¹¹, or —OR¹¹.

In another embodiment hereof R¹⁵ is independently selected from halogen,—CN, —CF₃, —C(O)OC₁-C₆-alkyl, and —COOH.

In another embodiment hereof R¹⁵ is independently selected from halogenor —C(O)OC₁-C₆-alkyl.

In another embodiment hereof R¹⁶ is independently selected from halogen,—C(O)OC₁-C₆-alkyl, —COOH, —NO₂, —OC₁-C₆-alkyl, —NH₂, C(═O) orC₁-C₆-alkyl.

In another embodiment hereof R¹⁶ is independently selected from halogen,—C(O)OC₁-C₆-alkyl, —COOH, —NO₂, or C₁-C₆-alkyl.

In another embodiment hereof the zinc-binding ligand is

wherein

-   -   R¹⁹ is hydrogen or C₁-C₆-alkyl,    -   R²⁰ is hydrogen or C₁-C₆-alkyl,    -   D, D¹ and F are a valence bond, C₁-C₆-alkylene or        C₁-C₆-alkenylene optionally substituted with one or more        substituents independently selected from R⁷²,    -   R⁷² is independently selected from hydroxy, C₁-C₆-alkyl, or        aryl,    -   E is C₁-C₆-alkyl, aryl or heteroaryl, wherein the aryl or        heteroaryl is optionally substituted with up to three        substituents R²¹, R²² and R²³,    -   G and G¹ are C₁-C₆-alkyl, aryl or heteroaryl, wherein the aryl        or heteroaryl is optionally substituted with up to three        substituents R²⁴, R²⁵ and R²⁶,    -   R¹⁷, R¹⁸, R²¹, R²², R²³, R²⁴, R²⁵ and R²⁶ are independently        selected from        -   hydrogen, halogen, —CN, —CH₂CN, —CHF₂, —CF₃, —OCF₃, —OCHF₂,            —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —SCF₃, —NO₂, ═O, —OR²⁷,            —NR²⁷R²⁸, —SR²⁷S(O)₂R²⁸, —S(O)₂NR²⁷R²⁸, —S(O)NR²⁷R²⁸,            —S(O)R², —S(O)₂R²⁷, —C(O)NR²⁷R²⁸, —OC(O)NR²⁷R²⁸,            —NR²⁷C(O)R²⁸, —NR²⁷C(O)OR²⁸, —CH₂C(O)NR²⁷R²⁸,            —OCH₂C(O)NR²⁷R²⁸, —CH₂OR²⁷, —CH₂N R²⁷R²⁸, —OC(O)R²⁷,            —OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷,            —C₂-C₆-alkenyl-C(═O)OR²⁷, —NR²⁷—C(═O)—C₁-C₆-alkyl-C(═O)OR²⁷,            —NR²⁷—C(═O)-C₁-C₆-alkenyl-C(═O)OR²⁷,            —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or            —C(O)OR²⁷,        -   C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl,        -   which may optionally be substituted with one or more            substituents independently selected from R²⁹,        -   aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C₁-C₆-alkoxy,            aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl,            heteroaryl, heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl            or heteroaryl-C₂-C₆-alkynyl,        -   of which the cyclic moieties optionally may be substituted            with one or more substituents selected from R³⁰,    -   R²⁷ and R²⁸ are independently selected from hydrogen,        C₁-C₆-alkyl, aryl-C₁-C₆-alkyl or aryl, or R²⁷ and R²⁸ when        attached to the same nitrogen atom together with the said        nitrogen atom may form a 3 to 8 membered heterocyclic ring        optionally containing one or two further heteroatoms selected        from nitrogen, oxygen and sulphur, and optionally containing one        or two double bonds,    -   R²⁹ is independently selected from halogen, —CN, —CF₃, —OCF₃,        —OR²⁷, and —NR²⁷R²⁸,    -   R³⁰ is independently selected from halogen, —C(O)OR²⁷, —CN,        —CF₃, —OCF₃, —NO₂, —OR²⁷, —NR²⁷R²⁸ and C₁-C₆-alkyl, or any        enantiomer, diastereomer, including a racemic mixture, tautomer        as well as a salt thereof with a pharmaceutically acceptable        acid or base.

In another embodiment hereof D is a valence bond.

In another embodiment hereof D is C₁-C₆-alkylene optionally substitutedwith one or more hydroxy, C₁-C₆-alkyl, or aryl.

In another embodiment hereof E is aryl or heteroaryl, wherein the arylor heteroaryl is optionally substituted with up to three substituentsindependently selected from R²¹, R²² and R²³.

In another embodiment hereof E is aryl optionally substituted with up tothree substituents independently selected from R²¹, R²² and R²³.

In another embodiment hereof E is selected from ArG1 and optionallysubstituted with up to three substituents independently selected fromR²¹, R²² and R²³.

In another embodiment hereof E is phenyl optionally substituted with upto three substituents independently selected from R²¹, R²² and R²³.

In another embodiment hereof the zinc-binding ligand is

In another embodiment hereof R²¹, R²² and R²³ are independently selectedfrom

-   -   hydrogen, halogen, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃,        —OCF₂CHF₂, —SCF₃, —NO₂, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —C(O)NR²⁷R²⁸,        —OC(O)NR²⁷R²⁸, —NR²⁷C(O)R²⁸, —NR²⁷C(O)OR²⁸, —CH₂C(O)NR²⁷R²⁸,        —OCH₂C(O)NR²⁷R²⁸, —CH₂OR²⁷, —CH₂NR²⁷R²⁸, —OC(O)R²⁷,        —OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷,        —C₂-C₆-alkenyl-C(═O)OR²⁷, —NR²⁷—C(═O)—C₁-C₆-alkyl-C(═O)OR²⁷,        —NR²⁷—C(═O)—C₁-C₆-alkenyl-C(═O)OR²⁷—,        —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or        —C(O)OR²⁷,    -   C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl,    -   which may optionally be substituted with one or more        substituents independently selected from R²⁹    -   aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C₁-C₆-alkoxy,        aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl,        heteroaryl, heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl or        heteroaryl-C₂-C₆-alkynyl,    -   of which the cyclic moieties optionally may be substituted with        one or more substituents selected from R³⁰.

In another embodiment hereof R²¹, R²² and R²³ are independently selectedfrom

-   -   hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²C(O)R²⁸,        —NR²⁷C(O)OR²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷,        —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷,        —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or        —C(O)OR²⁷,    -   C₁-C₆-alkyl optionally substituted with one or more substituents        independently selected from R²⁹    -   aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl,        heteroaryl, heteroaryl-C₁-C₆-alkyl,    -   of which the cyclic moieties optionally may be substituted with        one or more substituents selected from R³⁰.

In another embodiment hereof R²¹, R²² and R²³ are independently selectedfrom

-   -   hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸,        —NR²⁷C(O)OR²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷,        —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷,        —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or        —C(O)OR²⁷,    -   methyl, ethyl propyl optionally substituted with one or more        substituents independently selected from R²⁹    -   aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl,        heteroaryl, heteroaryl-C₁-C₆-alkyl    -   of which the cyclic moieties optionally may be substituted with        one or more substituents selected from R³⁰.

In another embodiment hereof R²¹, R²² and R²³ are independently selectedfrom

-   -   hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸,        —NR²⁷C(O)OR²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷,        —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷,        —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or        —C(O)OR²⁷,    -   methyl, ethyl propyl optionally substituted with one or more        substituents independently selected from R²⁹    -   ArG1, ArG1-O—, ArG1-C(O)—, ArG1-C₁-C₆-alkoxy, ArG1-C_(1-C)        ₆-alkyl, Het3, Het3-C₁-C₆-alkyl    -   of which the cyclic moieties optionally may be substituted with        one or more substituents selected from R³⁰.

In another embodiment hereof R²¹, R²² and R²³ are independently selectedfrom

-   -   hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸,        —NR²⁷C(O)OR²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷,        —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷,        —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or        —C(O)OR²⁷,    -   C₁-C₆-alkyl optionally substituted with one or more substituents        independently selected from R²⁹    -   phenyl, phenyloxy, phenyl-C₁-C₆-alkoxy, phenyl-C₁-C₆-alkyl,        of which the cyclic moieties optionally may be substituted with        one or more substituents selected from R³⁰.

In another embodiment hereof R¹⁹ is hydrogen or methyl.

In another embodiment hereof R¹⁹ is hydrogen.

In another embodiment hereof R²⁷ is hydrogen, C₁-C₆-alkyl or aryl.

In another embodiment hereof R²⁷ is hydrogen or C₁-C₆-alkyl.

In another embodiment hereof R²⁸ is hydrogen or C₁-C₆-alkyl.

In another embodiment hereof F is a valence bond.

In another embodiment hereof F is C₁-C₆-alkylene optionally substitutedwith one or more hydroxy, C₁-C₆-alkyl, or aryl.

In another embodiment hereof G is C₁-C₆-alkyl or aryl, wherein the arylis optionally substituted with up to three substituents R²⁴, R²⁵ andR²⁶.

In another embodiment hereof G is C₁-C₆-alkyl or ArG1, wherein the arylis optionally substituted with up to three substituents R²⁴, R²⁵ andR²⁶.

In another embodiment hereof G is C₁-C₆-alkyl.

In another embodiment hereof G is phenyl optionally substituted with upto three substituents R²⁴, R²⁵ and R²⁶.

In another embodiment hereof R²⁴, R²⁵ and R²⁶ are independently selectedfrom

-   -   hydrogen, halogen, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃,        —OCF₂CHF₂, —SCF₃, —NO₂, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —C(O)NR²⁷R²⁸,        —OC(O)NR²⁷R²⁸, —NR²⁷C(O)R²⁸, —NR²⁷C(O)OR²⁸, —CH₂C(O)NR²⁷R²⁸,        —OCH₂C(O)NR²⁷R²⁸, —CH₂OR²⁷, —CH₂NR²⁷R²⁸, —OC(O)R²⁷,        —OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷,        —C₂-C₆-alkenyl-C(═O)OR²⁷, —NR²⁷—C(═O)—C₁-C₆-alkyl-C(═O)OR²⁷,        —NR²⁷—C(═O)—C₁-C₆-alkenyl-C(═O)OR²⁷—,        —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or        —C(O)OR²⁷,    -   C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl,    -   which may optionally be substituted with one or more        substituents independently selected from R²⁹    -   aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C₁-C₆-alkoxy,        aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl,        heteroaryl, heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl or        heteroaryl-C₂-C₆-alkynyl,    -   of which the cyclic moieties optionally may be substituted with        one or more substituents selected from R³⁰.

In another embodiment hereof R²⁴, R²⁵ and R²⁶ are independently selectedfrom

-   -   hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸,        —NR²⁷C(O)OR²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷,        —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷,        —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or        —C(O)OR²⁷,    -   C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl,    -   which may optionally be substituted with one or more        substituents independently selected from R²⁹    -   aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C₁-C₆-alkoxy,        aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl,        heteroaryl, heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl or        heteroaryl-C₂-C₆-alkynyl,    -   of which the cyclic moieties optionally may be substituted with        one or more substituents selected from R³⁰.

In another embodiment hereof R²⁴, R²⁵ and R²⁶ are independently selectedfrom

-   -   hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸,        —NR²⁷C(O)OR²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷,        —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷,        —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or        —C(O)OR²⁷,    -   C₁-C₆-alkyl optionally substituted with one or more substituents        independently selected from R²⁹    -   aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl,        heteroaryl, heteroaryl-C₁-C₆-alkyl,    -   of which the cyclic moieties optionally may be substituted with        one or more substituents selected from R³⁰.

In another embodiment hereof R²¹, R²² and R²³ are independently selectedfrom

-   -   hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸,        —NR²⁷C(O)OR²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷,        —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷,        —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or        —C(O)OR²⁷,    -   methyl, ethyl propyl optionally substituted with one or more        substituents independently selected from R²⁹    -   ArG1, ArG1-O—, ArG1-C(O)—, ArG1-C₁-C₆-alkoxy, ArG1-C₁-C₆-alkyl,        Het3, Het3-C₁-C₆-alkyl        of which the cyclic moieties optionally may be substituted with        one or more substituents selected from R³⁰.

In another embodiment hereof R²¹, R²² and R²³ are independently selectedfrom

-   -   hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸,        —NR²⁷C(O)OR²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷,        —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷,        —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or        —C(O)OR²⁷,    -   methyl, ethyl propyl optionally substituted with one or more        substituents independently selected from R²⁹    -   ArG1, ArG1-O—, ArG1-C(O)—, ArG1-C₁-C₆-alkoxy, ArG1-C₁-C₆-alkyl,        Het3, Het3-C₁-C₆-alkyl    -   of which the cyclic moieties optionally may be substituted with        one or more substituents selected from R³⁰.

In another embodiment hereof R²¹, R²² and R²³ are independently selectedfrom

-   -   hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸,        —NR²⁷C(O)OR²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷,        —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷,        —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or        —C(O)OR²⁷,    -   methyl, ethyl propyl optionally substituted with one or more        substituents independently selected from R²⁹    -   ArG1, ArG1-O—, ArG1-C₁-C₆-alkoxy, ArG1-C₁-C₆-alkyl,        of which the cyclic moieties optionally may be substituted with        one or more substituents selected from R³⁰.

In another embodiment hereof R²⁰ is hydrogen or methyl.

In another embodiment hereof R²⁰ is hydrogen.

In another embodiment hereof R²⁷ is hydrogen, C₁-C₆-alkyl or aryl.

In another embodiment hereof R²⁷ is hydrogen or C₁-C₆-alkyl or ArG1.

In another embodiment hereof R²⁷ is hydrogen or C₁-C₆-alkyl.

In another embodiment hereof R²⁸ is hydrogen or C₁-C₆-alkyl.

In another embodiment hereof R¹⁷ and R¹⁸ are independently selected from

-   -   hydrogen, halogen, —CN, —CF₃, —OCF₃, —NO₂, —OR²⁷, —NR²⁷R²⁸,        —SR²⁷, —S(O)R²⁷, —S(O)R²⁷, —C(O)NR²⁷R²⁸, —CH₂OR²⁷, —OC(O)R²⁷,        —OC₁-C₆-alkyl-C(O)OR, —SC₁-C₆-alkyl-C(O)OR²⁷, or —C(O)OR²⁷,    -   C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, optionally        substituted with one or more substituents independently selected        from R²⁹    -   aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl,        heteroaryl, heteroaryl-C₁-C₆-alkyl,    -   of which the cyclic moieties optionally may be substituted with        one or more substituents selected from R³⁰.

In another embodiment hereof R¹⁷ and R¹⁸ are independently selected from

-   -   hydrogen, halogen, —CN, —CF₃, —NO₂, —OR²⁷, —NR²⁷R²⁸, or        —C(O)OR²⁷,    -   C₁-C₆-alkyl optionally substituted with one or more substituents        independently selected from R²⁹    -   aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl,        heteroaryl, heteroaryl-C₁-C₆-alkyl,    -   of which the cyclic moieties optionally may be substituted with        one or more substituents selected from R³⁰.

In another embodiment hereof R¹⁷ and R¹⁸ are independently selected from

-   -   hydrogen, halogen, —CN, —CF₃, —NO₂, —OR²⁷, —NR²⁷R²⁸, or        —C(O)OR²⁷    -   methyl, ethyl propyl optionally substituted with one or more        substituents independently selected from R²⁹    -   aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl,        heteroaryl, heteroaryl-C₁-C₆-alkyl    -   of which the cyclic moieties optionally may be substituted with        one or more substituents selected from R³⁰.

In another embodiment hereof R¹⁷ and R¹⁸ are independently selected from

-   -   hydrogen, halogen, —CN, —CF₃, —NO₂, —OR²⁷, —NR²⁷R²⁸, or        —C(O)OR²⁷    -   methyl, ethyl propyl optionally substituted with one or more        substituents independently selected from R²⁹    -   ArG1, ArG1-O—, ArG1-C(O)—, ArG1-C₁-C₆-alkoxy, ArG1-C₁-C₆-alkyl,        Het3, Het3-C₁-C₆-alkyl        of which the cyclic moieties optionally may be substituted with        one or more substituents selected from R³⁰.

In another embodiment hereof R¹⁷ and R¹⁸ are independently selected from

-   -   hydrogen, halogen, —CN, —CF₃, —NO₂, —OR²⁷, —NR²⁷R²⁸, or        —C(O)OR²⁷    -   C₁-C₆-alkyl optionally substituted with one or more substituents        independently selected from R²⁹    -   phenyl, phenyloxy, phenyl-C₁-C₆-alkoxy, phenyl-C₁-C₆-alkyl,        of which the cyclic moieties optionally may be substituted with        one or more substituents selected from R³⁰.

In another embodiment hereof R²⁷ is hydrogen or C₁-C₆-alkyl.

In another embodiment hereof R²⁷ is hydrogen, methyl or ethyl.

In another embodiment hereof R²⁸ is hydrogen or C₁-C₆-alkyl.

In another embodiment hereof R²⁸ is hydrogen, methyl or ethyl.

In another embodiment hereof R⁷² is —OH or phenyl.

In another embodiment hereof the zinc-binding ligand is

In another embodiment hereof the zinc-binding ligand is of the formH—I-Jwherein H is

wherein the phenyl, naphthalene or benzocarbazole rings are optionallysubstituted with one or more substituents independently selected fromR³¹

-   -   I is selected from        -   a valence bond,        -   —CH₂N(R³²)— or —SO₂N(R³³)—,        -               wherein Z¹ is S(O)₂ or CH₂, Z² is —NH—, —O— or —S—, and n is            1 or 2,    -   J is        -   C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, which may each            optionally be substituted with one or more substituents            selected from R³⁴,        -   Aryl, aryloxy, aryl-oxycarbonyl-, aroyl, aryl-C₁-C₆-alkoxy-,            aryl-C₁-C₆-alkyl-, aryl-C₂-C₆-alkenyl-, aryl-C₂-C₆-alkynyl-,            heteroaryl, heteroaryl-C₁-C₆-alkyl-,            heteroaryl-C₂-C₆-alkenyl- or heteroaryl-C₂-C₆-alkynyl-,            wherein the cyclic moieties are optionally substituted with            one or more substituents selected from R³⁷,        -   hydrogen,    -   R³¹ is independently selected from hydrogen, halogen, —CN,        —CH₂CN, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂,        —S(O)₂CF₃, —SCF₃, —NO₂, —OR³⁵, —C(O)R³⁵, —C(O)R³⁵, —NR³⁵R³⁶,        —SR³⁵, —NR³⁵S(O)₂R , —S(O)₂NR³⁵R³⁵, —S(O)NR³⁵R³⁶, —S(O)R³⁵,        —S(O)₂R³⁵, —C(O)NR³⁵R³⁶, —OC(O)NR³⁵R³⁶, —NR³⁵C(O)R³⁶,        —CH₂C(O)NR³⁵R³⁶, —OCH₂C(O)NR³⁵R³⁶, —CH₂OR³⁵, —CH₂NR³⁵R³⁵,        —OC(O)R³⁵, —OC₁-C₆-alkyl-C(O)OR³⁵,        —SC₁-C₆-alkyl-C(O)OR³⁵−C₂-C₆-alkenyl-C(═O)OR³⁵,        —NR³⁵—C(═)—C₁-C₆-alkyl-C(═O)OR³⁵,        —NR³⁵—C(═)—C₁-C₆-alkenyl-C(═O)OR³⁵—, C₁-C₆-alkyl, C₁-C₆-alkanoyl        or —C(O)OR³⁵,    -   R³² and R³³ are independently selected from hydrogen,        C₁-C₆-alkyl or C₁-C₆-alkanoyl,    -   R³⁴ is independently selected from halogen, —CN, —CF₃, —OCF₃,        —OR³⁵, and —NR³⁵R³⁶,    -   R³⁵ and R³⁶ are independently selected from hydrogen,        C₁-C₆-alkyl, aryl-C₁-C₆-alkyl or aryl, or R³⁵ and R³⁶ when        attached to the same nitrogen atom together with the said        nitrogen atom may form a 3 to 8 membered heterocyclic ring        optionally containing one or two further heteroatoms selected        from nitrogen, oxygen and sulphur, and optionally containing one        or two double bonds,    -   R³¹ is independently selected from halogen, —C(O)OR³⁵, —C(O)H,        —CN, —CF₃, —OCF₃, —NO₂, —OR³⁵, —NR³⁵R³⁶, C₁-C₆-alkyl or        C₁-C₆-alkanoyl,    -   or any enantiomer, diastereomer, including a racemic mixture,        tautomer as well as a salt thereof with a pharmaceutically        acceptable acid or base.

In another embodiment hereof the zinc-binding ligand is of the formH—I-J, wherein H is wherein the phenyl, naphthalene or benzocarbazolerings are optionally substituted with one

or more substituents independently selected from R³¹,

-   -   I is selected from        -   a valence bond,        -   —CH₂N(R³²)— or —SO₂N(R³³)—,        -               wherein Z¹ is S(O)₂ or CH₂, Z² is N, —O— or —S—, and n is 1            or 2,    -   J is        -   C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, which may each            optionally be substituted with one or more substituents            selected from R³⁴,        -   Aryl, aryloxy, aryl-oxycarbonyl-, aroyl, aryl-C₁-C₆-alkoxy-,            aryl-C₁-C₆-alkyl-, aryl-C₂-C₆-alkenyl-, aryl-C₂-C₆-alkynyl-,            heteroaryl, heteroaryl-C₁-C₆-alkyl-,            heteroaryl-C₂-C₆-alkenyl- or heteroaryl-C₂-C₆-alkynyl-,            wherein the cyclic moieties are optionally substituted with            one or more substituents selected from R³⁷,        -   hydrogen,    -   R³¹ is independently selected from hydrogen, halogen, —CN,        —CH₂CN, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂,        —S(O)₂CF₃, —SCF₃, —NO₂, —OR³⁵, —C(O)R³⁵, —NR³⁵R³⁶, —SR³⁵,        —NR³⁵S(O)₂R³⁶, —S(O)₂NR³⁵R³⁶, —S(O)NR³⁵R³⁶, —S(O)R³⁵,        —S(O)₂R³⁵R³⁶, —OC(O)NR³⁵R³⁶, —NR³⁵C(O)R³⁶, —CH₂C(O)NR³⁵R³⁶,        —OCH₂C(O)NR³⁵R³⁶, —CH₂OR³⁵, —CH₂NR³⁵R³⁶, —OC(O)R³⁵,        —OC₁-C₆-alkyl-C(O)OR³⁵,        —SC₁-C₆-alkyl-C(O)OR³⁵—C₂-C₆alkenyl-C(═O)OR³⁵,        —NR³⁵—C(═O)—C₁-C₆-alkyl-C(═O)OR³⁵,        —NR³⁵—C(═O)—C₁-C₆-alkenyl-C(═O)OR³⁵—, C₁-C₆-alkyl,        C₁-C₆-alkanoyl or —C(O)OR³⁵,    -   R³² and R³³ are independently selected from hydrogen,        C₁-C₆-alkyl or C₁-C₆-alkanoyl,    -   R³⁴is independently selected from halogen, —CN, —CF₃, —OCF₃,        —OR³⁵, and —NR³⁵R³⁶,    -   R³⁵ and R³⁶ are independently selected from hydrogen,        C₁-C₆-alkyl, aryl-C₁-C₆-alkyl or aryl, or R³⁵ and R³⁶ when        attached to the same nitrogen atom together with the said        nitrogen atom may form a 3 to 8 membered heterocyclic ring        optionally containing one or two further heteroatoms selected        from nitrogen, oxygen and sulphur, and optionally containing one        or two double bonds,    -   R³⁷ is independently selected from halogen, —C(O)OR³⁵, —C(O)H,        —CN, —CF₃, —OCF₃, —NO₂, —OR³⁵, —NR³⁵R³⁶, C₁-C₆-alkyl or        C₁-C₆-alkanoyl,    -   or any enantiomer, diastereomer, including a racemic mixture,        tautomer as well as a salt thereof with a pharmaceutically        acceptable acid or base,

With the proviso that R³¹ and J cannot both be hydrogen.

In another embodiment hereof H is

In another embodiment hereof H is

In another embodiment hereof H is

In another embodiment hereof I is a valence bond, —CH₂N(R³²)—, or—SO₂N(R³³)—.

In another embodiment hereof I is a valence bond.

In another embodiment hereof J is

-   -   hydrogen,    -   C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl,    -   which may optionally be substituted with one or more        substituents selected from halogen, —CN, —CF₃, —OCF₃, —OR³⁵, and        —NR³⁵R³⁶,    -   aryl, or heteroaryl, wherein the cyclic moieties are optionally        substituted with one or more substituents independently selected        from R³⁷.

In another embodiment hereof J is

-   -   hydrogen,    -   aryl or heteroaryl, wherein the cyclic moieties are optionally        substituted with one or more substituents independently selected        from R³⁷.

In another embodiment hereof J is

-   -   hydrogen,    -   ArG1 or Het3, wherein the cyclic moieties are optionally        substituted with one or more substituents independently selected        from R³⁷.

In another embodiment hereof J is

-   -   hydrogen,    -   phenyl or naphthyl optionally substituted with one or more        substituents independently selected from R³⁷.

In another embodiment hereof J is hydrogen.

In another embodiment hereof R³² and R³³ are independently selected fromhydrogen or C₁-C₆-alkyl.

In another embodiment hereof R³⁴ is hydrogen, halogen, —CN, —CF₃, —OCF₃,—SCF₃, —NO₂, —OR³⁵, —C(O)R³⁹, —NR³⁵R³⁶, —SR³⁵, —C(O)NR³⁵R³⁶,—OC(O)NR³⁵R³⁶, —NR³⁵, —OC(O)R³⁵, —OC₁-C₆-alkyl-C(O)OR³⁵,—SC₁-C₆-alkyl-C(O)OR³⁵ or —C(O)OR³⁵.

In another embodiment hereof R³⁴ is hydrogen, halogen, —CF₃, —NO₂,—OR³⁵, —NR³⁵R³⁶, —SR³⁵, —NR³⁵C(O)R³⁶, or —C(O)OR³⁵.

In another embodiment hereof R³⁴ is hydrogen, halogen, —CF₃, —NO₂,—OR³⁵, —NR³⁵R³⁶, or —NR³⁵C(O)R³⁶.

In another embodiment hereof R³⁴ is hydrogen, halogen, or —OR³⁵.

In another embodiment hereof R³⁵ and R³⁶ are independently selected fromhydrogen, C₁-C₆-alkyl, or aryl.

In another embodiment hereof R³⁵ and R³⁶ are independently selected fromhydrogen or C₁-C₆-alkyl.

In another embodiment hereof R³⁷ is halogen, —C(O)OR³⁵, —CN, —CF₃,—OR³⁵, —NR³⁵R³⁶, C₁-C₆-alkyl or C₁-C₆-alkanoyl.

In another embodiment hereof R³⁷ is halogen, —C(O)OR³⁵, —OR³⁵, —NR³⁵R³⁶,C₁-C₆-alkyl or C₁-C₆-alkanoyl.

In another embodiment hereof R³¹ is halogen, —C(O)OR³⁵ or —OR³⁵.

In another embodiment hereof the zinc-binding ligand is

wherein K is a valence bond, C₁-C₆-alkylene, —NH—C(═O)—U—,—C₁-C₆-alkyl-S—, —C₁-C₆-alkyl-O—, —C(═O)—, or —C(═O)—NH—, wherein anyC₁-C₆-alkyl moiety is optionally substituted with R³⁸,

-   -   U is a valence bond, C₁-C₆-alkenylene, —C₁-C₆-alkyl-O- or        C₁-C₆-alkylene wherein any C₁-C₆-alkyl moiety is optionally        substituted with C₁-C₆-alkyl,    -   R³⁸ is C₁-C₆-alkyl, aryl, wherein the alkyl or aryl moieties are        optionally substituted with one or more substituents        independently selected from R³⁹,    -   R³⁹ is independently selected from halogen, cyano, nitro, amino,    -   M is a valence bond, arylene or heteroarylene, wherein the aryl        or heteroaryl moieties are optionally substituted with one or        more substituents independently selected from R⁴⁰,    -   R⁴⁰ is selected from        -   hydrogen, halogen, —CN, —CH₂CN, —CHF₂, —CF₃, —OCF₃, —OCHF₂,            —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —OS(O)₂CF₃, —SCF₃, —NO₂,            —OR⁴¹, —NR⁴¹R⁴², —SR⁴¹, —NR⁴¹S(O)₂R⁴², —S(O)₂NR⁴¹R⁴²,            —S(O)NR⁴¹R⁴², —S(O)R⁴¹, —S(O)₂R⁴¹, —OS(O)₂ R⁴¹,            —C(O)NR⁴¹R⁴², —OC(O)NR⁴¹R⁴², —NR⁴¹C(O)R⁴², —CH₂C(O)NR⁴¹R⁴²,            —OC₁-C₆-alkyl-C(O)NR⁴¹ R⁴², —CH₂OR⁴¹, —CH₂OC(O)R⁴¹,            —CH₂NR⁴¹R⁴², —OC(O)R⁴¹, —OC₁-C₆-alkyl-C(O)OR⁴¹,            —OC₁-C₆-alkyl-OR⁴¹, —S—C₁-C₆-alkyl-C(O)OR⁴¹,            —C₂-C₆-alkenyl-C(═O)OR⁴¹, —NR⁴¹-C(═O)-C₁-C₆-alkyl-C(═O)OR⁴¹,            —NR⁴¹-C(═O)-C₁-C₆-alkenyl-C(═O)OR⁴¹ , —C(O)OR⁴¹,            —C₂-C₆-alkenyl-C(═O)R⁴¹, ═O, —NH—C(═O)—O—C₁-C₆-alkyl, or            —NH—C(═O)—C(═O)—O—C₁-C₆-alkyl,        -   C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, which may each            optionally be substituted with one or more substituents            selected from R⁴³,        -   aryl, aryloxy, aryloxycarbonyl, aroyl, arylsulfanyl,            aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl,            aroyl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl,            heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl or            heteroaryl-C₂-C₆-alkynyl, wherein the cyclic moieties            optionally may be substituted with one or more substituents            selected from R⁴⁴,    -   R⁴¹ and R⁴² are independently selected from hydrogen, —OH,        C₁-C₆-alkyl, C₁-C₆-alkenyl, aryl-C₁-C₆-alkyl or aryl, wherein        the alkyl moieties may optionally be substituted with one or        more substituents independently selected from R⁴⁵, and the aryl        moieties may optionally be substituted with one or more        substituents independently selected from R⁴⁶; R⁴¹ and R⁴² when        attached to the same nitrogen atom may form a 3 to 8 membered        heterocyclic ring with the said nitrogen atom, the heterocyclic        ring optionally containing one or two further heteroatoms        selected from nitrogen, oxygen and sulphur, and optionally        containing one or two double bonds,    -   R⁴³ is independently selected from halogen, —CN, —CF₃, —OCF₃,        —OR⁴¹, and —NR⁴¹R⁴²    -   R⁴⁴ is independently selected from halogen, —C(O)OR⁴¹,        —CH₂C(O)OR⁴¹, —CH₂OR⁴¹, —CN, —CF₃, —OCF₃, —NO₂, —OR⁴¹, —NR⁴¹R⁴²        and C₁-C₆-alkyl,    -   R⁴⁵ is independently selected from halogen, —CN, —CF₃, —OCF₃,        —O—C₁-C₆-alkyl, —C(O)—O—C₁-C₆-alkyl, —COOH and —NH₂,    -   R⁴⁵ is independently selected from halogen, —C(O)OC₁-C₆-alkyl,        —COOH, —CN, —CF₃, —OCF₃, —NO₂, —OH, —OC₁-C₆-alkyl, —NH₂, C(═O)        or C₁-C₆-alkyl,    -   Q is a valence bond, C₁-C₆-alkylene, —C₁-C₆-alkyl-O—,        —C₁-C₆-alkyl-NH—, —NH—C₁-C₆-alkyl, —NH—C(═O)—, —C(═O)—NH—,        —O—C₁-C₆-alkyl, —C(═O)—, or —C₁-C₆-alkyl-C(═O)—N(R⁴⁷)— wherein        the alkyl moieties are optionally substituted with one or more        substituents independently selected from R⁴⁸,    -   R⁴⁷ and R⁴⁸ are independently selected from hydrogen,        C₁-C₆-alkyl, aryl optionally substituted with one or more R⁴⁹,    -   R⁴⁹ is independently selected from halogen and —COOH,    -   T is        -   hydrogen,        -   C₁-C₆-alkyl, C₂-C₆-alkenyl , C₂-C₆-alkynyl,            C₁-C₆-alkyloxy-carbonyl, wherein the alkyl alkenyl and            alkynyl moieties are optionally substituted with one or more            substituents independently selected from R⁵⁰,        -   aryl, aryloxy, aryloxy-carbonyl, aryl-C₁-C₆-alkyl, aroyl,            aryl-C₁-C₆-alkoxy, aryl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkyny-,            heteroaryl, heteroaryl-C₁-C₆-alkyl,            heteroaryl-C₂-C₆-alkenyl, heteroaryl-C₂-C₆-alkynyl,        -   wherein any alkyl, alkenyl , alkynyl, aryl and heteroaryl            moiety is optionally substituted with one or more            substituents independently selected from R⁵⁰,    -   R⁵⁰ is C₁-C₆-alkyl, C₁-C₆-alkoxy, aryl, aryloxy,        aryl-C₁-C₆-alkoxy, —C(═O)—NH—C₁-C₆-alkyl-aryl        —C(═O)—NR^(50A)—C₁-C₆-alkyl,        —C(═O)—NH—(CH₂CH₂O)_(m)C₁-C₆-alkyl-COOH, heteroaryl,        heteroaryl-C₁-C₆-alkoxy, —C₁-C₆-alkyl-COOH, —O—C₁-C₆-alkyl-COOH,        —S(O)₂R⁵¹, —C₂-C₆-alkenyl-COOH, —OR⁵¹, —NO₂, halogen, —COOH,        —CF₃, —CN, ═O, —N(R⁵¹R⁵²), wherein m is 1, 2, 3 or 4, and        wherein the aryl or heteroaryl moieties are optionally        substituted with one or more R⁵³, and the alkyl moieties are        optionally substituted with one or more R^(50B).    -   R^(50A) and R^(50B) are independently selected from        —C(O)OC₁-C₆-alkyl, —COOH, —C₁-C₆-alkyl-C(O)OC₁-C₆-alkyl,        —C₁-C₆-alkyl-COOH, or C₁-C₆-alkyl,    -   R⁵¹ and R⁵² are independently selected from hydrogen and        C₁-C₆-alkyl,    -   R⁵³ is independently selected from C₁-C₆-alkyl, C₁-C₆-alkoxy,        —C₁-C₆-alkyl-COOH, —C₂-C₆-alkenyl-COOH, —OR⁵¹, —NO₂, halogen,        —COOH, —CF₃, —CN, or —N(R⁵¹R⁵²),    -   or any enantiomer, diastereomer, including a racemic mixture,        tautomer as well as a salt thereof with a pharmaceutically        acceptable acid or base.

In another embodiment hereof K is a valence bond, C₁-C₆-alkylene,—NH—C(═O)—U—, —C₁-C₆-alkyl-S—, —C₁-C₆-alkyl-O—, or —C(═O)—, wherein anyC₁-C₆-alkyl moiety is optionally substituted with R³⁸.

In another embodiment hereof K is a valence bond, C₁-C₆-alkylene,—NH—C(═O)—U—, —C₁-C₆-alkyl-S—, or —C₁-C₆-alkyl-O, wherein anyC₁-C₆-alkyl moiety is optionally substituted with R³⁸.

In another embodiment hereof K is a valence bond, C₁-C₆-alkylene, or—NH—C(═O)—U, wherein any C₁-C₆-alkyl moiety is optionally substitutedwith R³⁸.

In another embodiment hereof K is a valence bond or C₁-C₆-alkylene,wherein any C₁-C₆-alkyl moiety is optionally substituted with R³⁸.

In another embodiment hereof K is a valence bond or —NH—C(═O)—U.

In another embodiment hereof K is a valence bond.

In another embodiment hereof U is a valence bond or —C₁-C₆-alkyl-O—.

In another embodiment hereof U is a valence bond.

In another embodiment hereof M is arylene or heteroarylene, wherein thearylene or heteroarylene moieties are optionally substituted with one ormore substituents independently selected from R⁴⁰.

In another embodiment hereof M is ArG1 or Het1, wherein the arylene orheteroarylene moieties are optionally substituted with one or moresubstituents independently selected from R⁴⁰.

In another embodiment hereof M is ArG1 or Het2, wherein the arylene orheteroarylene moieties are optionally substituted with one or moresubstituents independently selected from R⁴⁰.

In another embodiment hereof M is ArG1 or Het3, wherein the arylene orheteroarylene moieties are optionally substituted with one or moresubstituents independently selected from R⁴⁰.

In another embodiment hereof M is phenylene optionally substituted withone or more substituents independently selected from R⁴⁰.

In another embodiment hereof M is indolylene optionally substituted withone or more substituents independently selected from R⁴⁰.

In another embodiment hereof M is

In another embodiment hereof M is carbazolylene optionally substitutedwith one or more substituents independently selected from R⁴⁰.

In another embodiment hereof M is

In another embodiment hereof R⁴⁰ is selected from

-   -   hydrogen, halogen, —CN, —CF₃, —OCF₃, —NO₂, —OR⁴¹, —NR⁴¹R⁴²,        —SR⁴¹, —S(O)₂R⁴¹, —NR⁴¹C(O)R⁴², —OC₁-C₆-alkyl-C(O)N R⁴¹R⁴²,        —C₂-C₆-alkenyl-C(═O)OR⁴¹, —C(O)OR⁴¹, ═O,        —NH—C(═O)—O—C₁-C₆-alkyl, or —NH—C(═O)—C(═O)—O—C₁-C₆-alkyl,    -   C₁-C₆-alkyl or C₂-C₆-alkenyl which may each optionally be        substituted with one or more substituents independently selected        from R⁴³,    -   aryl, aryloxy, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl,        aryl-C₂-C₆-alkenyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, or        heteroaryl-C₂-C₆-alkenyl, wherein the cyclic moieties optionally        may be substituted with one or more substituents selected from        R⁴⁴.

In another embodiment hereof R⁴⁰ is selected from

-   -   hydrogen, halogen, —CN, —CF₃, —OCF₃, —NO₂, —OR⁴¹, —NR⁴¹R⁴²,        —SR⁴¹, —S(O)₂R⁴¹, —NR⁴¹C(O)R⁴², —OC₁-C₆-alkyl-C(O)NR⁴¹R⁴²,        —C₂-C₆-alkenyl-C(═O)OR⁴¹, —C(O)OR⁴¹, ═O,        —NH—C(═O)—O—C₁-C₆-alkyl, or —NH—C(═O)—C(═O)—O—C₁-C₆-alkyl,    -   C₁-C₆-alkyl or C₂-C₆-alkenyl which may each optionally be        substituted with one or more substituents independently selected        from R⁴³,    -   ArG1, ArG1-O—, ArG1-C₁-C₆-alkoxy, ArG1-C₁-C₆-alkyl,        ArG1-C₂-C₆-alkenyl, Het3, Het3-C₁-C₆-alkyl, or        Het3-C₂-C₆-alkenyl, wherein the cyclic moieties optionally may        be substituted with one or more substituents selected from R⁴⁴.

In another embodiment hereof R⁴⁰ is selected from

-   -   hydrogen, halogen, —CF₃, —NO₂, —OR⁴¹—NR⁴¹R⁴²—C(O)OR⁴¹, ═O, or        —NR⁴¹C(O)R⁴²,    -   C₁-C₆-alkyl,    -   ArG1.

In another embodiment hereof R⁴⁰ is hydrogen.

In another embodiment hereof R⁴⁰ is selected from

-   -   Halogen, —NO₂, —OR⁴¹, —NR⁴¹R⁴², —C(O)OR⁴¹, or —NR⁴¹C(O)R⁴²,    -   Methyl,    -   Phenyl.

In another embodiment hereof R⁴¹ and R⁴² are independently selected fromhydrogen, C₁-C6-alkyl, or aryl, wherein the aryl moieties may optionallybe substituted with halogen or —COOH.

In another embodiment hereof R⁴¹ and R⁴² are independently selected fromhydrogen, methyl, ethyl, or phenyl, wherein the phenyl moieties mayoptionally be substituted with halogen or —COOH.

In another embodiment hereof Q is a valence bond, C₁-C₆-alkylene,—C₁-C₆-alkyl-O—, —C₁-C₆-alkyl-NH—, —NH—C₁-C₆-alkyl, —NH—C(═O)—,—C(═O)—NH—, —O—C₁-C₆-alkyl, —C(═O)—, or —C₁-C₆-alkyl-C(═O)—N(R⁴⁷)—wherein the alkyl moieties are optionally substituted with one or moresubstituents independently selected from R⁴⁸.

In another embodiment hereof Q is a valence bond, —CH₂—, —CH₂—CH₂—,—CH₂—O—, —CH₂—CH₂—O—, —CH₂—NH—, —CH₂—CH₂—NH—, —NH—CH₂—, —NH—CH₂—CH₂—,—NH—C(═O)—, —C(═O)—NH—, —O—CH₂—. —O—CH₂—CH₂—, or —C(═O)—.

In another embodiment hereof R⁴⁷ and R⁴⁸ are independently selected fromhydrogen, methyl and phenyl.

In another embodiment hereof T is

-   -   Hydrogen,    -   C₁-C₆-alkyl optionally substituted with one or more substituents        independently selected from R⁵⁰,    -   aryl, aryl-C₁-C₆-alkyl, heteroaryl, wherein the alkyl, aryl and        heteroaryl moieties are optionally substituted with one or more        substituents independently selected from R⁵⁰.

In another embodiment hereof T is

-   -   hydrogen,    -   C₁-C₆-alkyl optionally substituted with one or more substituents        independently selected from R⁵⁰,    -   ArG1, ArG1-C₁-C₆-alkyl, Het3, wherein the alkyl, aryl and        heteroaryl moieties are optionally substituted with one or more        substituents independently selected from R⁵⁰.

In another embodiment hereof T is

-   -   hydrogen,    -   C₁-C₆-alkyl, optionally substituted with one or more        substituents independently selected from R⁵⁰,    -   phenyl, phenyl-C₁-C₆-alkyl, wherein the alkyl and phenyl        moieties are optionally substituted with one or more        substituents independently selected from R⁵⁰.

In another embodiment hereof T is phenyl substituted with R⁵⁰.

In another embodiment hereof R⁵⁰ is C₁-C₆-alkyl, C₁-C₆-alkoxy, aryl,aryloxy, aryl-C₁-C₆-alkoxy, —C(═O)—NH—C₁-C₆-alkyl-aryl,—C(═O)—NR^(50A)—C₁-C₆-alkyl, —C(═O)—NH—(CH₂CH₂O)_(m)C₁-C₆-alkyl-COOH,heteroaryl, —C₁-C₆-alkyl-COOH, —O—C₁-C₆-alkyl-COOH, —S(O)₂R⁵¹,—C₂-C₆-alkenyl-COOH, —OR⁵¹, —NO₂, halogen, —COOH, —CF₃, —CN, ═O,—N(R⁵¹R⁵²), wherein the aryl or heteroaryl moieties are optionallysubstituted with one or more R⁵³.

In another embodiment hereof R⁵⁰ is C₁-C₆-alkyl, C₁-C₆-alkoxy, aryl,aryloxy, —C(═O)—NR^(50A)—C₁-C₆-alkyl,—C(═O)—NH—(CH₂CH₂O)_(m)C₁-C₆-alkyl-COOH, aryl-C₁-C₆-alkoxy, —OR⁵¹, —NO₂,halogen, —COOH, —CF₃, wherein any aryl moiety is optionally substitutedwith one or more R⁵³.

In another embodiment hereof R⁵⁰ is C₁-C₆-alkyl, aryloxy,—C(═O)—NR^(50A)—C₁-C₆-alkyl, —C(═O)—NH—(CH₂CH₂O)_(m)C₁-C₆-alkyl-COOH,aryl-C₁-C₆-alkoxy , —OR⁵¹, halogen, —COOH, —CF₃, wherein any aryl moietyis optionally substituted with one or more R⁵³.

In another embodiment hereof R⁵⁰ is C₁-C₆-alkyl, ArG1-O—,—C(═O)—NR^(50A)—C₁-C₆-alkyl, —C(═O)—NH—(CH₂CH₂O)_(m)C₁-C₆-alkyl-COOH,ArG1-C₁-C₆-alkoxy , —OR⁵¹, halogen, —COOH, —CF₃, wherein any aryl moietyis optionally substituted with one or more R⁵³.

In another embodiment hereof R⁵⁰ is —C(═O)—NR^(50A)—CH₂,—C(═O)—NH—(CH₂CH₂O)₂CH₂I—COOH, or —C(═O)—NR^(50A)CH₂CH₂.

In another embodiment hereof R⁵⁰ is phenyl, methyl or ethyl.

In another embodiment hereof R⁵⁰ is methyl or ethyl.

In another embodiment hereof m is 1 or 2.

In another embodiment hereof R⁵¹ is methyl.

In another embodiment hereof R⁵³ is C₁-C₆-alkyl, C₁-C₆-alkoxy, —OR⁵¹,halogen, or —CF₃.

In another embodiment hereof R^(50A) is —C(O)OCH₃, —C(O)OCH₂CH₃—COOH,—CH₂C(O)OCH₃, —CH₂C(O)OCH₂CH₃, —CH₂CH₂C(O)OCH₃, —CH₂CH₂C(O)OCH₂CH₃,—CH₂COOH, methyl, or ethyl.

In another embodiment hereof R^(50B) is —C(O)OCH₃, —C(O)OCH₂CH₃—COOH,—CH₂C(O)OCH₃, —CH₂C(O)OCH₂CH₃, —CH₂CH₂C(O)OCH₃, —CH₂CH₂C(O)OCH₂CH₃,—CH₂COOH, methyl, or ethyl.

In another embodiment hereof the zinc-binding ligand is

wherein V is C₁-C₆-alkyl, aryl, heteroaryl, aryl-C₁₋₆-alkyl- oraryl-C₂₋₆-alkenyl-, wherein the alkyl or alkenyl is optionallysubstituted with one or more substituents independently selected fromR⁵⁴, and the aryl or heteroaryl is optionally substituted with one ormore substituents independently selected from R⁵⁵,

-   -   R⁵⁴ is independently selected from halogen, —CN, —CF₃, —OCF₃,        aryl, —COOH and —NH₂,    -   R⁵⁵ is independently selected from        -   hydrogen, halogen, —CN, —CH₂CN, —CHF₂, —CF₃, —OCF₃, —OCHF₂,            —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —OS(O)₂CF₃, —SCF₃, —NO₂,            —OR⁵⁶, —NR⁵⁶R⁵⁷, —SR⁵⁶, —NR⁵⁶S(O)₂R⁵⁷, —S(O)₂NR⁵⁶R⁵⁷,            —S(O)NR⁵⁶R⁵⁷, —S(O)R⁵⁶, —S(O)₂R⁵⁶, —OS(O)₂ R⁵⁶,            —C(O)NR⁵⁶R⁵⁷, —OC(O)NR⁵⁶R⁵⁷, —NR⁵⁶C(O)R⁵⁷, —CH₂C(O)NR⁵⁶R⁵⁷,            —OC₁-C₆-alkyl-C(O)NR⁵⁶R⁵⁷, —CH₂OR⁵⁶, —CH₂OC(O)R⁵⁶,            —CH₂NR⁵⁶R⁵⁷, —OC(O)R⁵⁶, —OC₁-C₆-alkyl-C(O)OR⁵⁶,            —OC₁-C₆-alkyl-OR⁵⁶, —SC₁-C₆-alkyl-C(O)OR⁵⁶,            —C₂-C₆-alkenyl-C(═O)OR⁵⁶, —NR⁵⁶—C(═O)—C₁-C₆-alkyl-C(═O)OR⁵⁶,            —NR⁵⁶—C(═O)—C₁-C₆-alkenyl-C(═O)OR⁵⁶, —C(O)OR⁵⁶, or            —C₂-C₆-alkenyl-C(═O)R⁵⁶,        -   C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl,        -   which may optionally be substituted with one or more            substituents selected from R⁵⁸,        -   aryl, aryloxy, aryloxycarbonyl, aroyl, arylsulfanyl,            aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl,            aroyl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl,            heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl or            heteroaryl-C₂-C₆-alkynyl,        -   of which the cyclic moieties optionally may be substituted            with one or more substituents selected from R⁵⁹,    -   R⁵⁶ and R⁵⁷ are independently selected from hydrogen, OH, CF₃,        C₁-C₁₂-alkyl, aryl-C₁-C₆-alkyl, —C(═O)—C₁-C₆-alkyl or aryl,        wherein the alkyl groups may optionally be substituted with one        or more substituents independently selected from R⁶⁰, and the        aryl groups may optionally be substituted with one or more        substituents independently selected from R⁶¹; R⁵⁶ and R⁵⁷ when        attached to the same nitrogen atom may form a 3 to 8 membered        heterocyclic ring with the said nitrogen atom, the heterocyclic        ring optionally containing one or two further heteroatoms        selected from nitrogen, oxygen and sulphur, and optionally        containing one or two double bonds,    -   R⁵⁸ is independently selected from halogen, —CN, —CF₃, —OCF₃,        —OR⁵⁶, and —NR⁵⁶R⁵⁷,    -   R⁵⁹ is independently selected from halogen, —C(O)OR⁵⁶,        —CH₂C(O)OR⁵⁶, —CH₂OR⁵⁶, —CN, —CF₃, —OCF₃, —NO₂, —OR⁵⁶, —NR⁵⁶R⁵⁷        and C₁-C₆-alkyl,    -   R⁶⁰ is independently selected from halogen, —CN, —CF₃, —OCF₃,        —OC₁-C₆-alkyl, —C(O)OC₁-C₆-alkyl, —C(═O)—R⁶², —COOH and —NH₂,    -   R⁶¹ is independently selected from halogen, —C(O)OC₁-C₆-alkyl,        —COOH, —CN, —CF₃, —OCF₃, —NO₂, —OH, —OC₁-C₆-alkyl, —NH₂, C(═O)        or C₁-C₆-alkyl,    -   R⁶² is C₁-C₆-alkyl, aryl optionally substituted with one or more        substituents independently selected from halogen, or heteroaryl        optionally substituted with one or more C₁-C₆-alkyl        independently,    -   or any enantiomer, diastereomer, including a racemic mixture,        tautomer as well as a salt thereof with a pharmaceutically        acceptable acid or base.

In another embodiment hereof V is aryl, heteroaryl, or aryl-C₁₋₆-alkyl-,wherein the alkyl is optionally substituted with one or moresubstituents independently selected R⁵⁴, and the aryl or heteroaryl isoptionally substituted with one or more substituents independentlyselected from R⁵⁵.

In another embodiment hereof V is aryl, Het1, or aryl-C₁₋₆-alkyl-,wherein the alkyl is optionally substituted with one or moresubstituents independently selected from R⁵⁴, and the aryl or heteroarylmoiety is optionally substituted with one or more substituentsindependently selected from R⁵⁵.

In another embodiment hereof V is aryl, Het2, or aryl-C₁₋₆-alkyl-,wherein the alkyl is optionally substituted with one or moresubstituents independently selected from R⁵⁴, and the aryl or heteroarylmoiety is optionally substituted with one or more substituentsindependently selected from R⁵⁵.

In another embodiment hereof V is aryl, Het3, or aryl-C₁₋₆-alkyl-,wherein the alkyl is optionally substituted with one or moresubstituents independently selected from R⁵⁴, and the aryl or heteroarylmoiety is optionally substituted with one or more substituentsindependently selected from R⁵⁵.

In another embodiment hereof V is aryl optionally substituted with oneor more substituents independently selected from R⁵⁵.

In another embodiment hereof V is ArG1 optionally substituted with oneor more substituents independently selected from R⁵⁵.

In another embodiment hereof V is phenyl, naphthyl or anthranyloptionally substituted with one or more substituents independentlyselected from R⁵⁵.

In another embodiment hereof V is phenyl optionally substituted with oneor more substituents independently selected from R⁵⁵.

In another embodiment hereof R⁵⁵ is independently selected from

-   -   halogen, C₁-C₆-alkyl, —CN, —OCF₃, —CF₃, —NO₂, —OR⁵⁶, —NR⁵⁶R⁵⁷,        —NR⁵⁶C(O)R⁵⁷ —SR⁵⁶, —OC₁-C₈-alkyl-C(O)OR⁵⁶, or —C(O)OR⁵⁶,    -   C₁-C₆-alkyl optionally substituted with one or more substituents        independently selected from R⁵⁸    -   aryl, aryl-C₁-C₆-alkyl, heteroaryl, or heteroaryl-C₁-C₆-alkyl    -   of which the cyclic moieties optionally may be substituted with        one or more substituents independently selected from R⁵⁹.

In another embodiment hereof R⁵⁵ is independently selected from

-   -   halogen, C₁-C₆-alkyl, —CN, —OCF₃, —CF₃, —NO₂, —OR⁵⁶, —NR⁵⁶R⁵⁷,        —NR⁵⁶C(O)R⁵⁷ —SR⁵⁶, —OC₁-C₈-alkyl-C(O)OR⁵⁶, or —C(O)OR⁵⁶    -   C₁-C₆-alkyl optionally substituted with one or more substituents        independently selected from R⁵⁸    -   ArG1, ArG1-C₁-C₆-alkyl, Het3, or Het3-C₁-C₆-alkyl    -   of which the cyclic moieties optionally may be substituted with        one or more substituents independently selected from R⁵⁹.

In another embodiment hereof R⁵⁵ is independently selected from halogen,—OR⁵⁶, —NR⁵⁶R⁵⁷, —C(O)OR⁵⁶, —OC₁-C₈-alkyl-C(O)OR⁵⁶, —NR⁵⁶C(O)R⁵⁷ orC₁-C₆-alkyl.

In another embodiment hereof R⁵⁵ is independently selected from halogen,—OR⁵⁶, —NR⁵⁶R⁵⁷, —C(O)OR⁵⁶, —OC₁-C₈-alkyl-C(O)OR⁵⁶, —NR⁵⁶C(O)R⁵⁷, methylor ethyl.

In another embodiment hereof R⁵⁶ and R⁵⁷ are independently selected fromhydrogen, CF₃, C₁-C₁₂-alkyl, or —C(═O)—C₁-C₆-alkyl; R⁵⁶ and R⁵⁷ whenattached to the same nitrogen atom may form a 3 to 8 memberedheterocyclic ring with the said nitrogen atom.

In another embodiment hereof R⁵⁶ and R⁵⁷ are independently selected fromhydrogen or C₁-C₁₂-alkyl, R⁵⁶ and R⁵⁷ when attached to the same nitrogenatom may form a 3 to 8 membered heterocyclic ring with the said nitrogenatom.

In another embodiment hereof R⁵⁶ and R⁵⁷ are independently selected fromhydrogen or methyl, ethyl, propyl butyl, R⁵⁶ and R⁵⁷ when attached tothe same nitrogen atom may form a 3 to 8 membered heterocyclic ring withthe said nitrogen atom.

In another embodiment hereof the zinc-binding ligand is

wherein AA is C₁-C₆-alkyl, aryl, heteroaryl, aryl-C₁₋₆alkyl- oraryl-C₂₋₆-alkenyl-, wherein the alkyl or alkenyl is optionallysubstituted with one or more substituents independently selected fromR⁶³, and the aryl or heteroaryl is optionally substituted with one ormore substituents independently selected from R⁶⁴,

-   -   R⁶³ is independently selected from halogen, —CN, —CF₃, —OCF₃,        aryl, —COOH and —NH₂,    -   R⁶⁴ is independently selected from        -   hydrogen, halogen, —CN, —CH₂CN, —CHF₂, —CF₃, —OCF₃, —OCHF₂,            —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —OS(O)₂CF₃, —SCF₃, —NO₂,            —OR⁶⁵, —NR⁶⁵R⁶⁶, —SR⁶⁵, —NR⁶⁵S(O)₂R⁶⁶, —S(O)₂NR⁶⁵R⁶⁶,            —S(O)NR⁶⁵R⁶⁶, —S(O)R⁶⁵, —S(O)₂R⁶⁵, —OS(O)₂ R⁶⁵,            —C(O)NR⁶⁵R⁶⁶, —OC(O)NR⁶⁵R⁶⁶, —NR⁶⁵C(O)R⁶⁶, —CH₂C(O)NR⁶⁵R⁶⁶,            —OC₁-C₆-alkyl-C(O)NR⁶⁵R⁶⁶, —CH₂OR⁶⁵, —CH₂OC(O)R⁶⁵,            —CH₂NR⁶⁵R⁶⁶, —OC(O)R⁶⁵, —OC₁-C₆-alkyl-C(O)OR⁶⁵,            —OC₁-C₆-alkyl-OR⁶⁵, —SC₁-C₆-alkyl-C(O)OR⁶⁵,            —C₂-C₆-alkenyl-C(═O)OR⁶⁵, —NR⁶⁵—C(═O)—C₁-C₆-alkyl-C(═O)OR⁶⁵,            —NR⁶⁵—C(═O)—C₁-C₆-alkenyl-C(═O)OR⁶⁵, —C(O)OR⁶⁵, or            —C₂-C₆-alkenyl-C(═O)R⁶⁵,        -   C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, each of which            may optionally be substituted with one or more substituents            selected from R⁶¹,    -   aryl, aryloxy, aryloxycarbonyl, aroyl, arylsulfanyl,        aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl,        aroyl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl,        heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-a Ikenyl or        heteroaryl-C₂-C₆-alkynyl,        -   of which the cyclic moieties optionally may be substituted            with one or more substituents selected from R⁶⁸,    -   R⁶⁵ and R⁶⁶ are independently selected from hydrogen, OH, CF₃,        C₁-C₁₂-alkyl, aryl-C₁-C₆-alkyl, —C(═O)—R⁶⁹, aryl or heteroaryl,        wherein the alkyl groups may optionally be substituted with one        or more substituents selected from R⁷⁰, and the aryl and        heteroaryl groups may optionally be substituted with one or more        substituents independently selected from R⁷¹; R⁶⁵ and R⁶⁶ when        attached to the same nitrogen atom may form a 3 to 8 membered        heterocyclic ring with the said nitrogen atom, the heterocyclic        ring optionally containing one or two further heteroatoms        selected from nitrogen, oxygen and sulphur, and optionally        containing one or two double bonds,    -   R⁶⁷ is independently selected from halogen, —CN, —CF₃, —OCF₃,        —OR⁶⁵, and —NR⁶⁵R⁶⁶,    -   R⁶⁸ is independently selected from halogen, —C(O)OR⁶⁵,        —CH₂C(O)OR⁶⁵, —CH₂OR⁶⁵, —CN, —CF₃, —OCF₃, —NO₂, —OR⁶⁵, —NR⁶⁵R⁶⁶        and C₁-C₆-alkyl,    -   R⁶⁹ is independently selected from C₁-C₆-alkyl, aryl optionally        substituted with one or more halogen, or heteroaryl optionally        substituted with one or more C₁-C₆-alkyl,    -   R⁷⁰ is independently selected from halogen, —CN, —CF₃, —OCF₃,        —OC₁-C₆-alkyl, —C(O)OC₁-C₆-alkyl, —COOH and —NH₂,    -   R⁷¹ is independently selected from halogen, —C(O)OC₁-C₆-alkyl,        —COOH, —CN, —CF₃, —OCF₃, —NO₂, —OH, —OC₁-C₆-alkyl, —NH₂, C(═O)        or C₁-C₆-alkyl,    -   or any enantiomer, diastereomer, including a racemic mixture,        tautomer as well as a salt thereof with a pharmaceutically        acceptable acid or base.

In another embodiment hereof AA is aryl, heteroaryl or aryl-C₁₋₆-alkyl-,wherein the alkyl is optionally substituted with one or more R⁶³, andthe aryl or heteroaryl is optionally substituted with one or moresubstituents independently selected from R⁶⁴.

In another embodiment hereof AA is aryl or heteroaryl optionallysubstituted with one or more substituents independently selected fromR⁶⁴.

In another embodiment hereof AA is ArG1 or Het1 optionally substitutedwith one or more substituents independently selected from R⁶⁴.

In another embodiment hereof AA is ArG1 or Het2 optionally substitutedwith one or more substituents independently selected from R⁶⁴.

In another embodiment hereof AA is ArG1 or Het3 optionally substitutedwith one or more substituents independently selected from R⁶⁴.

In another embodiment hereof AA is phenyl, naphtyl, anthryl, carbazolyl,thienyl, pyridyl, or benzodioxyl optionally substituted with one or moresubstituents independently selected from R⁶⁴.

In another embodiment hereof AA is phenyl or naphtyl optionallysubstituted with one or more substituents independently selected fromR⁶⁴.

In another embodiment hereof R⁶⁴ is independently selected fromhydrogen, halogen, —CF₃, —OCF₃, —OR⁶⁵, —NR⁶⁵R⁶⁶, C₁-C₆-alkyl ,—OC(O)R⁶⁵, —OC₁-C₆-alkyl-C(O)OR⁶⁵, alkenyl, aryloxy or aryl, whereinC₁-C₆-alkyl is optionally substituted with one or more substituentsindependently selected from R⁶⁷, and the cyclic moieties optionally aresubstituted with one or more substituents independently selected fromR⁶⁸.

In another embodiment hereof R⁶⁴ is independently selected from halogen,—CF₃, —OCF₃, —OR⁶⁵, —NR⁶⁵R⁶⁶, methyl, ethyl, propyl, —OC(O)R⁶⁵,—OCH₂—C(O)OR⁶⁵, —OCH₂—CH₂—C(O)OR⁶⁵, phenoxy optionally substituted withone or more substituents independently selected from R⁶⁸.

In another embodiment hereof R⁶⁵ and R⁶⁶ are independently selected fromhydrogen, CF₃, C₁-C₁₂-alkyl, aryl, or heteroaryl optionally substitutedwith one or more substituents independently selected from R⁷¹.

In another embodiment hereof R⁶⁵ and R⁶⁶ are independently hydrogen,C₁-C₁₂-alkyl, aryl, or heteroaryl optionally substituted with one ormore substituents independently selected from R⁷¹.

In another embodiment hereof R⁶⁵ and R⁶⁶ are independently hydrogen,methyl, ethyl, propyl, butyl, 2,2-dimethyl-propyl, ArG1 or Het1optionally substituted with one or more substituents independentlyselected from R⁷¹.

In another embodiment hereof R⁶⁵ and R⁶⁶ are independently hydrogen,methyl, ethyl, propyl, butyl, 2,2-dimethyl-propyl, ArG1 or Het2optionally substituted with one or more substituents independentlyselected from R⁷¹.

In another embodiment hereof R⁶⁵ and R⁶⁶ are independently hydrogen,methyl, ethyl, propyl, butyl, 2,2-dimethyl-propyl, ArG1 or Het3optionally substituted with one or more substituents independentlyselected from R⁷¹.

In another embodiment hereof R⁶⁵ and R⁶⁶ are independently hydrogen,methyl, ethyl, propyl, butyl, 2,2-dimethyl-propyl, phenyl, naphtyl,thiadiazolyl optionally substituted with one or more R⁷¹ independently;or isoxazolyl optionally substituted with one or more substituentsindependently selected from R⁷¹.

In another embodiment hereof R⁷¹ is halogen or C₁-C₆-alkyl.

In another embodiment hereof R⁷¹ is halogen or methyl.

The following aspects are also provided by the present invention,wherein the compounds of the invention may be any of the above describedembodiments.

In one aspect the invention provides a pharmaceutical compositionwherein the insulin is rapid acting insulin.

In another embodiment the invention provides a pharmaceuticalcomposition wherein the insulin is selected from the group consisting ofhuman insulin, an analogue thereof, a derivative thereof, andcombinations of any of these.

In another embodiment the invention provides a pharmaceuticalcomposition wherein the insulin is an analogue of human insulin selectedfrom the group consisting of

-   -   i. An analogue wherein position B28 is Asp, Lys, Leu, Val, or        Ala and position B29 is Lys or Pro; and    -   ii. des(B28-B30), des(B27) or des(B30) human insulin.

In another embodiment the invention provides a pharmaceuticalcomposition wherein the insulin is an analogue of human insulin whereinposition B28 is Asp or Lys, and position B29 is Lys or Pro.

In another embodiment the invention provides a pharmaceuticalcomposition wherein the insulin is des(B30) human insulin.

In another embodiment the invention provides a pharmaceuticalcomposition wherein the insulin is is an analogue of human insulinwherein position B3 is Lys and position B29 is Glu or Asp.

In another embodiment the invention provides a pharmaceuticalcomposition wherein the insulin is a derivative of human insulin havingone or more lipophilic substituents.

In another embodiment the invention provides a pharmaceuticalcomposition wherein the insulin derivative is selected from the groupconsisting of B29-N^(ε)-myristoyl-des(B30) human insulin,B29-N^(ε)-palmitoyl-des(B30) human insulin, B29-N^(ε)-myristoyl humaninsulin, B29-N^(ε)-palmitoyl human insulin, B28-N^(ε)-myristoylLYS^(B28) Pro^(B29) human insulin, B28-N^(ε)-palmitoyl Lys^(B28)Pro^(B29) human insulin, B30-N^(ε)-myristoyl-Thr^(B29)LyS^(B30) humaninsulin, B30-N^(ε)-palmitoyl-Thr^(B29)Lys^(B30) human insulin,B29-N^(ε)-(N-palmitoyl-γ-glutamyl)-des(B30) human insulin,B29-N^(ε)-(N-lithocholyl-γ-glutamyl)-des(B30) human insulin,B29-N^(ε)-(ω-carboxyheptadecanoyl)-des(B30) human insulin andB29-N^(ε)-(ω-carboxyheptadecanoyl) human insulin.

In another embodiment the invention provides a pharmaceuticalcomposition wherein the insulin derivative isB29-N^(ε)-myristoyl-des(B30) human insulin.

In another embodiment the invention provides a pharmaceuticalcomposition comprising 2-6 moles zinc²⁺ ions per mole insulin.

In another embodiment the invention provides a pharmaceuticalcomposition comprising 2-3 moles zinc²⁺ ions per mole insulin.

In another embodiment the invention provides a pharmaceuticalcomposition further comprising at least 3 molecules of a phenoliccompound per insulin hexamer.

In another embodiment the invention provides a pharmaceuticalcomposition further comprising an isotonicity agent.

In another embodiment the invention provides a pharmaceuticalcomposition further comprising a buffer substance.

A method of stabilising an insulin composition comprising adding azinc-binding ligand to the insulin composition.

A method of treating type 1 or type 2 diabetes comprising administeringto a patient in need thereof a pharmaceutically effective dose of aninsulin composition.

In one embodiment of the invention the concentration of added ligand forthe zinc site is between 0.2 and 10 times that of zinc ion in thepreparation. In another embodiment the concentration is between 0.5 and5 times that of zinc ion. In another embodiment the ligand concentrationis identical to that of zinc ion in the preparation.

The compounds of the present invention may be chiral, and it is intendedthat any enantiomers, as separated, pure or partially purifiedenantiomers or racemic mixtures thereof are included within the scope ofthe invention.

Furthermore, when a double bond or a fully or partially saturated ringsystem or more than one centre of asymmetry or a bond with restrictedrotatability is present in the molecule diastereomers may be formed. Itis intended that any diastereomers, as separated, pure or partiallypurified diastereomers or mixtures thereof are included within the scopeof the invention.

Furthermore, some of the compounds of the present invention may exist indifferent tautomeric forms and it is intended that any tautomeric forms,which the compounds are able to form, are included within the scope ofthe present invention.

The present invention also encompasses pharmaceutically acceptable saltsof the present compounds. Such salts include pharmaceutically acceptableacid addition salts, pharmaceutically acceptable metal salts, ammoniumand alkylated ammonium salts. Acid addition salts include salts ofinorganic acids as well as organic acids. Representative examples ofsuitable inorganic acids include hydrochloric, hydrobromic, hydroiodic,phosphoric, sulphuric, nitric acids and the like. Representativeexamples of suitable organic acids include formic, acetic,trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric,fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, picric,pyruvic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic,pamoic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic,palmitic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic,p-toluenesulfonic acids and the like. Further examples ofpharmaceutically acceptable inorganic or organic acid addition saltsinclude the pharmaceutically acceptable salts listed in J. Pharm. Sci.1977, 66, 2, which is incorporated herein by reference. Examples ofmetal salts include lithium, sodium, potassium, magnesium salts and thelike. Examples of ammonium and alkylated ammonium salts includeammonium, methyl-, dimethyl-, trimethyl-, ethyl-, hydroxyethyl-,diethyl-, n-butyl-, sec-butyl-, tert-butyl-, tetramethylammonium saltsand the like.

Also intended as pharmaceutically acceptable acid addition salts are thehydrates, which the present compounds, are able to form.

Furthermore, the pharmaceutically acceptable salts comprise basic aminoacid salts such as lysine, arginine and ornithine.

The acid addition salts may be obtained as the direct products ofcompound synthesis. In the alternative, the free base may be dissolvedin a suitable solvent containing the appropriate acid, and the saltisolated by evaporating the solvent or otherwise separating the salt andsolvent.

The compounds of the present invention may form solvates with standardlow molecular weight solvents using methods well known to the personskilled in the art. Such solvates are also contemplated as being withinthe scope of the present invention.

In one embodiment of the invention the stabilized preparations are usedin connection with insulin pumps. The insulin pumps may be prefilled anddisposable, or the insulin compositions may be supplied from a reservoirwhich is removable. Insulin pumps may be skin-mounted or carried, andthe path of the insulin composition from the storage compartment of thepump to the patient may be more or less tortuous. The elevatedtemperature and increased physical stress the insulin composition isthus exposed to challenges the stability of the constituent insulin.Non-limiting examples of insulin pumps are disclosed in U.S. Pat. No.5,957,895, 5,858,001, 4,468,221, 4,468,221, 5,957,895, 5,858,001,6,074,369, 5,858,001, 5,527,288, and U.S. Pat. No. 6,074,369.

In another embodiment the stabilized preparations are used in connectionwith pen-like injection devices, which may be prefilled and disposable,or the insulin compositions may be supplied from a reservoir which isremovable. Non-limiting examples of pen-like injection devices areFlexPen®, InnoLet®, InDuo™, Innovo®.

In a further embodiment stabilized preparations are used in connectionwith devices for pulmonary administration of aqueous insulincompositions, a non-limiting example of which is the AerX® device.

In one aspect of the invention, the ligands are added to rapid actinginsulin. The resulting preparations have improved physical and chemicalstability while still retaining a high rate of absorbtion fromsubcutaneous tissue.

The present invention also relates to pharmaceutical compositions forthe treatment of diabetes in a patient in need of such a treatmentcomprising an R-state hexamer of insulin according to the inventiontogether with a pharmaceutically acceptable carrier.

In one embodiment of the invention the insulin composition comprises 60to 3000 nmol/ml of insulin.

In another embodiment of the invention the insulin composition comprises240 to 1200 nmol/ml of insulin.

In another embodiment of the invention the insulin composition comprisesabout 600 nmol/ml of insulin.

Zinc ions may be present in an amount corresponding to 13 to 33 μgZn/100 U insulin, more preferably 15 to 26 μg Zn/100 U insulin.

Insulin formulations of the invention are usually administered frommulti-dose containers where a preservative effect is desired. Sincephenolic preservatives also stabilize the R-state hexamer theformulations may contain up to 50 mM of phenolic molecules. Non-limitingexamples of phenolic molecules are phenol, m-cresol, chloro-cresol,thymol, 7-hydroxyindole or any mixture thereof.

In one embodiment of the invention 0.5 to 4.0 mg/ml of phenolic compoundmay be employed.

In another embodiment of the invention 0.6 to 4.0 mg/ml of m-cresol maybe employed.

In another embodiment of the invention 0.5 to 4.0 mg/ml of phenol may beemployed.

In another embodiment of the invention 1.4 to 4.0 mg/ml of phenol may beemployed.

In another embodiment of the invention 0.5 to 4.0 mg/ml of a mixture ofm-cresol or phenol may be employed.

In another embodiment of the invention 1.4 to 4.0 mg/ml of a mixture ofm-cresol or phenol may be employed.

The pharmaceutical composition may further comprise a buffer substance,such as a TRIS, phosphate, glycine or glycylglycine (or anotherzwitterionic substance) buffer, an isotonicity agent, such as NaCl,glycerol, mannitol and/or lactose. Chloride would be used at moderateconcentrations, in one embodiment of the invention up to 50 mM to avoidcompetition with the zinc-site ligands of the present invention. Inanother embodiment the chloride concentration would be from 3 to 20 mM.

The in vivo action of insulin may be modified by the addition ofphysiologically acceptable agents that increase the viscosity of thepharmaceutical composition. Thus, the pharmaceutical compositionaccording to the invention may furthermore comprise an agent whichincreases the viscosity, such as polyethylene glycol, polypropyleneglycol, copolymers thereof, dextrans and/or polylactides.

In one embodiment the insulin composition of the invention comprisesbetween 0.0005% by weight and 1% by weight of a non-ionic orzwitter-ionic surfactant, for example tween 20 or Polox 188. A nonionicdetergent can be added to stabilise insulin against fibrillation duringstorage and handling.

The insulin composition of the present invention may have a pH value inthe range of 3.0 to 8.5, e.g. 7.4 to 7.9.

EXAMPLES

The following examples and general procedures refer to intermediatecompounds and final products identified in the specification and in thesynthesis schemes. The preparation of the compounds of the presentinvention is described in detail using the following examples, but thechemical reactions described are disclosed in terms of their generalapplicability to the preparation of compounds of the invention.Occasionally, the reaction may not be applicable as described to eachcompound included within the disclosed scope of the invention. Thecompounds for which this occurs will be readily recognised by thoseskilled in the art. In these cases the reactions can be successfullyperformed by conventional modifications known to those skilled in theart, that is, by appropriate protection of interfering groups, bychanging to other conventional reagents, or by routine modification ofreaction conditions. Alternatively, other reactions disclosed herein orotherwise conventional will be applicable to the preparation of thecorresponding compounds of the invention. In all preparative methods,all starting materials are known or may easily be prepared from knownstarting materials. All temperatures are set forth in degrees Celsiusand unless otherwise indicated, all parts and percentages are by weightwhen referring to yields and all parts are by volume when referring tosolvents and eluents.

HPLC-MS (Method A)

The following instrumentation was used:

-   -   Hewlett Packard series 1100 G1312A Bin Pump    -   Hewlett Packard series 1100 Column compartment    -   Hewlett Packard series 1100 G13 15A DAD diode array detector    -   Hewlett Packard series 1100 MSD

The instrument was controlled by HP Chemstation software.

The HPLC pump was connected to two eluent reservoirs containing:

-   -   A: 0.01% TFA in water    -   B: 0.01% TFA in acetonitrile

The analysis was performed at 40° C. by injecting an appropriate volumeof the sample (preferably 1 μL) onto the column, which was eluted with agradient of acetonitrile.

The HPLC conditions, detector settings and mass spectrometer settingsused are given in the following table. Column Waters Xterra MS C-18 × 3mm id Gradient 10%-100% acetonitrile lineary during 7.5 min at 1.0mL/min Detection UV: 210 nm (analog output from DAD) MS Ionisation mode:API-ES Scan 100-1000 amu step 0.1 amuHPLC-MS (Method B)

The following instrumentation was used:

-   -   Sciex API 100 Single quadropole mass spectrometer    -   Perkin Elmer Series 200 Quard pump    -   Perkin Elmer Series 200 autosampler    -   Applied Biosystems 785A UV detector    -   Sedex 55 evaporative light scattering detector

A Valco column switch with a Valco actuator controlled by timed eventsfrom the pump.

The Sciex Sample control software running on a Macintosh PowerPC 7200computer was used for the instrument control and data acquisition.

The HPLC pump was connected to four eluent reservoirs containing:

-   -   A: Acetonitrile    -   B: Water    -   C: 0.5% TFA in water    -   D: 0.02 M ammonium acetate

The requirements for samples are that they contain approximately 500μg/mL of the compound to be analysed in an acceptable solvent such asmethanol, ethanol, acetonitrile, THF, water and mixtures thereof. (Highconcentrations of strongly eluting solvents will interfere with thechromatography at low acetonitrile concentrations.)

The analysis was performed at room temperature by injecting 20 μL of thesample solution on the column, which was eluted with a gradient ofacetonitrile in either 0.05% TFA or 0.002 M ammonium acetate. Dependingon the analysis method varying elution conditions were used.

The eluate from the column was passed through a flow splittingT-connector, which passed approximately 20 μL/min through approx. 1 m.75μ fused silica capillary to the API interface of API 100 spectrometer.

The remaining 1.48 mL/min was passed through the UV detector and to theELS detector.

During the LC-analysis the detection data were acquired concurrentlyfrom the mass spectrometer, the UV detector and the ELS detector.

The LC conditions, detector settings and mass spectrometer settings usedfor the different methods are given in the following table. Column YMCODS-A 120Å s − 5μ 3 mm × 50 mm id Gradient 5%-90% acetonitrile in 0.05%TFA linearly during 7.5 min at 1.5 mL/min Detection UV: 214 nm ELS: 40°C. MS Experiment: Start: 100 amu Stop: 800 amu Step: 0.2 amu Dwell:0.571 msec Method: Scan 284 times = 9.5 min

HPLC-MS (Method C) The following instrumentation is used:

-   -   Hewlett Packard series 1100 G1312A Bin Pump    -   Hewlett Packard series 1100 Column compartment    -   Hewlett Packard series 1100 G1315A DAD diode array detector    -   Hewlett Packard series 1100 MSD    -   Sedere 75 Evaporative Light Scattering detector

The instrument is controlled by HP Chemstation software.

The HPLC pump is connected to two eluent reservoirs containing: A 0.01%TFA in water B 0.01% TFA in acetonitrile

The analysis is performed at 40° C. by injecting an appropriate volumeof the sample (preferably 1 μl) onto the column which is eluted with agradient of acetonitrile.

The HPLC conditions, detector settings and mass spectrometer settingsused are given in the following table. Column Waters Xterra MS C-18 × 3mm id 5 μm Gradient 5%-100% acetonitrile linear during 7.5 min at 1.5ml/min Detection 210 nm (analogue output from DAD) ELS (analogue outputfrom ELS) MS ionisation mode API-ES Scan 100-1000 amu step 0.1 amu

After the DAD the flow is divided yielding approximately 1 ml/min to theELS and 0.5 ml/min to the MS.

HPLC-MS (Method D)

The following instrumentation was used:

-   -   Sciex API 150 Single Quadropole mass spectrometer    -   Hewlett Packard Series 1100 G1312A Bin pump    -   Gilson 215 micro injector    -   Hewlett Packard Series 1100 G1315A DAD diode array detector    -   Sedex 55 evaporative light scattering detector

A Valco column switch with a Valco actuator controlled by timed eventsfrom the pump.

The Sciex Sample control software running on a Macintosh Power G3computer was used for the instrument control and data acquisition.

The HPLC pump was connected to two eluent reservoirs containing:

-   -   A: Acetonitrile containing 0.05% TFA    -   B: Water containing 0.05% TFA

The requirements for the samples are that they contain approximately 500μg/ml of the compound to be analysed in an acceptable solvent such asmethanol, ethanol, acetonitrile, THF, water and mixtures thereof. (Highconcentrations of strongly eluting solvents will interfere with thechromatography at low acetonitrile concentrations.)

The analysis was performed at room temperature by injecting 20 μL of thesample solution on the column, which was eluted with a gradient ofacetonitrile in 0.05% TFA

The eluate from the column was passed through a flow splittingT-connector, which passed approximately 20 μl/min through approx. 1 m75μ fused silica capillary to the API interface of API 150 spectrometer.

The remaining 1.48 ml/min was passed through the UV detector and to theELS detector. During the LC-analysis the detection data were acquiredconcurrently from the mass spectrometer, the UV detector and the ELSdetector.

The LC conditions, detector settings and mass spectrometer settings usedfor the different methods are given in the following table. ColumnWaters X-terra C18 5μ 3 mm × 50 mm id Gradient 5%-90% acetonitrile in0.05% TFA linearly during 7.5 min at 1.5 ml/min Detection UV: 214 nmELS: 40° C. MS Experiment: Start: 100 amu Stop: 800 amu Step: 0.2 amuDwell: 0.571 msec Method: Scan 284 times = 9.5 min

EXAMPLES

4-[(1H-Benzotriazole-5-carbonyl)amino]benzoic acid methyl ester (5.2 g,17.6 mmol) was dissolved in THF (60 mL) and methanol (10 mL) was addedfollowed by 1N sodium hydroxide (35 mL). The mixture was stirred at roomtemperature for 16 hours and then 1N hydrochloric acid (45 mL) wasadded. The mixture was added water (200 mL) and extracted with ethylacetate (2×500 mL). The combined organic phases were evaporated in vacuoto afford 0.44 g of 4-[(1H-benzotriazole-5-carbonyl)amino]benzoic acid.By filtration of the aqueous phase a further crop of4-[(1H-benzotriazole-5-carbonyl)amino]benzoic acid was isolated (0.52g).

¹H-NMR (DMSO-d₆): δ 7.97 (4H, s), 8.03 (2H, m), 8.66 (1H, bs), 10.7 (1H,s), 12.6 (1H, bs); HPLC-MS (Method A): m/z: 283 (M+1); Rt=1.85 min.General Procedure (A) for Preparation of Compounds of General FormulaI₁:

wherein D, E and R¹⁹ are as defined above, and E is optionallysubstituted with up to three substituents R²¹, R²² and R²³ independentlyas defined above.

The carboxylic acid of 1H-benzotriazole-5-carboxylic acid is activated,ie the OH functionality is converted into a leaving group L (selectedfrom eg fluorine, chlorine, bromine, iodine, 1-imidazolyl,1,2,4-triazolyl, 1-benzotriazolyloxy, 1-(4-aza benzotriazolyl)oxy,pentafluorophenoxy, N-succinyloxy3,4-dihydro-4-oxo-3-(1,2,3-benzotriazinyl)oxy, benzotriazole 5-COO, orany other leaving group known to act as a leaving group in acylationreactions. The activated benzotriazole-5-carboxylic acid is then reactedwith R²—(CH₂)_(n)—B′ in the presence of a base. The base can be eitherabsent (i.e. R²—(CH₂)_(n)—B′ acts as a base) or triethylamine,N-ethyl-N,N.-diisopropylamine, N-methylmorpholine, 2,6-lutidine,2,2,6,6-tetramethylpiperidine, potassium carbonate, sodium carbonate,caesium carbonate or any other base known to be useful in acylationreactions. The reaction is performed in a solvent solvent such as THF,dioxane, toluene, dichloromethane, DMF, NMP or a mixture of two or moreof these. The reaction is performed between 0° C. and 80° C., preferablybetween 20° C. and 40° C. When the acylation is complete, the product isisolated by extraction, filtration, chromatography or other methodsknown to those skilled in the art.

The general procedure (A) is further illustrated in the followingexample:

0102-0000-1020Example 9 (General Procedure (A))PEM1H-Benzotriazole-5-carboxylic acid phenylamide

Benzotriazole-5-carboxylic acid (856 mg), HOAt (715 mg) and EDAC (1.00g) were dissolved in DMF (17.5 mL) and the mixture was stirred at roomtemperature 1 hour. A 0.5 mL aliqot of this mixture was added to aniline(13.7 μL, 0.15 mmol) and the resulting mixture was vigorously shaken atroom temperature for 16 hours. 1N hydrochloric acid (2 mL) and ethylacetate (1 mL) were added and the mixture was vigorously shaken at roomtemperature for 2 hours. The organic phase was isolated and concentratedin vacuo to afford the title compound.

HPLC-MS (Method B): m/z: 239 (M+1); Rt=3.93 min.

The compounds in the following examples were similarly made. Optionally,the compounds may be isolated by filtration or by chromatography.

0102-0000-1019Example 10 (General Procedure (A))PEM1H-Benzotriazole-5-carboxylic acid (4-methoxyphenyl)amide

HPLC-MS (Method A): m/z: 269 (M+1) & 291 (M+23); Rt=2.41 min

HPLC-MS (Method B): m/z: 239 (M+1); Rt=3.93 min.

0102-0000-1021 Example 11 (General Procedure (A))PEM{4-[(1H-Benzotriazole-5-carbonyl)amino]phenyl}carbamic acid tert-butylester

HPLC-MS (Method B): m/z: 354 (M+1); Rt=4.58 min.

0102-0000-1022Example 12 (General Procedure (A))PEM1H-Benzotriazole-5-carboxylic acid (4-acetylaminophenyl)amide

HPLC-MS (Method B): m/z: 296 (M+1); Rt=3.32 min.

0102-0000-1023Example 13 (General Procedure (A))PEM1H-Benzotriazole-5-carboxylic acid (3-fluorophenyl)amide

HPLC-MS (Method B): m/z: 257 (M+1); Rt=4.33 min.

0102-0000-1024Example 14 (General Procedure (A))PEM1H-Benzotriazole-5-carboxylic acid (2-chlorophenyl)amide

HPLC-MS (Method B): m/z: 273 (M+1); Rt=4.18 min.

0102-0000-1025Example 15 (General Procedure (A))PEM4-[(1H-Benzotriazole-5-carbonyl)amino]benzoic acid methyl ester

HPLC-MS (Method A):m/z: 297 (M+1); Rt: 2.60 min. HPLC-MS (Method B):m/z: 297 (M+1); Rt=4.30 min.

0102-0000-1026Example 16 (General Procedure (A))PEM1H-Benzotriazole-5-carboxylic acid (4-butylphenyl)amide

HPLC-MS (Method B): m/z: 295 (M+1); Rt=5.80 min.

0102-0000-1027Example 17 (General Procedure (A))PEM1H-Benzotriazole-5-carboxylic acid (1-phenylethyl)amide

HPLC-MS (Method B): m/z: 267 (M+1); Rt=4.08 min.

0102-0000-1028Example 18 (General Procedure (A))PEM1H-Benzotriazole-5-carboxylic acid benzylamide

HPLC-MS (Method B): m/z: 253 (M+1); Rt=3.88 min.

0102-0000-1029Example 19 (General Procedure (A))PEM1H-Benzotriazole-5-carboxylic acid 4-chlorobenzylamide

HPLC-MS (Method B): m/z: 287 (M+1); Rt=4.40 min.

0102-0000-1030Example 20 (General Procedure (A))PEM1H-Benzotriazole-5-carboxylic acid 2-chlorobenzylamide

HPLC-MS (Method B): m/z: 287 (M+1); Rt=4.25 min.

0102-0000-1031 Example 21 (General Procedure (A))PEM1H-Benzotriazole-5-carboxylic acid 4-methoxybenzylamide

HPLC-MS (Method B): m/z: 283 (M+1); Rt=3.93 min.

0102-0000-1032Example 22 (General Procedure (A))PEM1H-Benzotriazole-5-carboxylic acid 3-methoxybenzylamide

HPLC-MS (Method B): m/z: 283 (M+1); Rt=3.97 min.

0102-0000-1033Example 23 (General Procedure (A))PEM1H-Benzotriazole-5-carboxylic acid (1,2-diphenylethyl)amide

HPLC-MS (Method B): m/z: 343 (M+1); Rt=5.05 min.

0102-0000-1034Example 24 (General Procedure (A))PEM1H-Benzotriazole-5-carboxylic acid 3-bromobenzylamide

HPLC-MS (Method B): m/z: 331 (M+1); Rt=4.45 min.

0102-0000-1035Example 25 (General Procedure (A))PEM4-{[(1H-Benzotriazole-5-carbonyl)amino]methyl}benzoic acid

HPLC-MS (Method B): m/z: 297 (M+1); Rt=3.35 min.

0102-0000-1036Example 26 (General Procedure (A))PEM1H-Benzotriazole-5-carboxylic acid phenethylamide

HPLC-MS (Method B): m/z: 267 (M+1); Rt=4.08 min.

0102-0000-1037Example 27 (General Procedure (A))PEM1H-Benzotriazole-5-carboxylic acid [2-(4-chlorophenyl)ethyl]amide

HPLC-MS (Method B): m/z: 301 (M+1); Rt=4.50 min.

0102-0000-1038Example 28 (General Procedure (A))PEM1H-Benzotriazole-5-carboxylic acid [2-(4-methoxyphenyl)ethyl]amide

HPLC-MS (Method B): m/z: 297 (M+1); Rt=4.15 min.

0102-0000-1039Example 29 (General Procedure (A))PEM1H-Benzotriazole-5-carboxylic acid [2-(3-methoxyphenyl)ethyl]amide

HPLC-MS (Method B): m/z: 297 (M+1); Rt=4.13 min.

0102-0000-1040Example 30 (General Procedure (A))PEM1H-Benzotriazole-5-carboxylic acid [2-(3-chlorophenyl)ethyl]amide

HPLC-MS (Method B): m/z: 301 (M+1); Rt=4.55 min.

0102-0000-1041 Example 31 (General Procedure (A))PEM1H-Benzotriazole-5-carboxylic acid (2,2-diphenylethyl)amide

HPLC-MS (Method B): m/z: 343 (M+1); Rt=5.00 min.

0102-0000-1042Example 32 (General Procedure (A))PEM1H-Benzotriazole-5-carboxylic acid (3,4-dichlorophenyl)methylamide

HPLC-MS (Method B): m/z: 321 (M+1); Rt=4.67 min.

0102-0000-1043Example 33 (General Procedure (A))PEM1H-Benzotriazole-5-carboxylic acid methylphenylamide

HPLC-MS (Method B): m/z: 253 (M+1); Rt=3.82 min.

0102-0000-1044Example 34 (General Procedure (A))PEM1H-Benzotriazole-5-carboxylic acid benzylmethylamide

HPLC-MS (Method B): m/z: 267 (M+1); Rt=4.05 min.

0102-0000-1046Example 35 (General Procedure (A))PEM1H-Benzotriazole-5-carboxylic acid[2-(3-chloro-4-methoxyphenyl)ethyl]methyl-amide

HPLC-MS (Method B): m/z: 345 (M+1); Rt=4.37 min.

0102-0000-1046Example 36 (General Procedure (A))PEM1H-Benzotriazole-5-carboxylic acid methylphenethylamide

HPLC-MS (Method B): m/z: 281 (M+1); Rt=4.15 min.

0102-0000-1047Example 37 (General Procedure (A))PEM1H-Benzotriazole-5-carboxylic acid[2-(3,4-dimethoxyphenyl)ethyl]methylamide

HPLC-MS (Method B): m/z: 341 (M+1); Rt=3.78 min;

0102-0000-1048Example 38 (General Procedure (A))PEM1H-Benzotriazole-5-carboxylic acid (2-hydroxy-2-phenylethyl)methylamide

HPLC-MS (Method B): m/z: 297 (M+1); Rt=3.48 min.

Example 39 (General procedure (A)) 1H-Benzotriazole-5-carboxylic acid(3-bromophenyl)amide

HPLC-MS (Method A): m/z: 317 (M+1); Rt=3.19 min.

Example 40 (General procedure (A)) 1H-Benzotriazole-5-carboxylic acid(4-bromophenyl)amide

HPLC-MS (Method A): m/z: 317 (M+1); Rt=3.18 min.

Example 41 (General procedure (A)){4-[(1H-Benzotriazole-5-carbonyl)amino]benzoylamino}acetic acid

HPLC-MS (Method A): m/z: 340 (M+1); Rt=1.71 min.

Example 42 (General procedure (A)){4-[(1H-Benzotriazole-5-carbonyl)amino]phenyl}acetic acid

HPLC-MS (Method A): m/z: 297 (M+1); Rt=2.02 min.

Example 43 (General procedure (A))3-{4-[(1H-Benzotriazole-5-carbonyl)amino]phenyl}acrylic acid

HPLC-MS (Method A): m/z: 309 (M+1); Rt=3.19 min.

Example 44 (General procedure (A)){3-[(1H-Benzotriazole-5-carbonyl)amino]phenyl}acetic acid

HPLC-MS (Method A): m/z: 297 (M+1); Rt=2.10 min.

Example 45 (General procedure (A))2-{4-[(1H-Benzotriazole-5-carbonyl)amino]phenoxy}-2-methylpropionic acid

HPLC-MS (Method A): m/z: 341 (M+1); Rt=2.42 min.

Example 46 (General procedure (A))3-{4-[(1H-Benzotriazole-5-carbonyl)amino]benzoylamino}propionic acid

HPLC-MS (Method A): m/z: 354 (M+1); Rt=1.78 min.

Example 47 (General procedure (A))3-{4-[(1H-Benzotriazole-5-carbonyl)amino]phenyl}propionic acid

HPLC-MS (Method A): m/z: 311 (M+1); Rt=2.20 min.

Example 48 (General procedure (A)) 1H-Benzotriazole-5-carboxylic acid(4-benzyloxyphenyl)amide

HPLC-MS (Method A): m/z: 345 (M+1); Rt=3.60 min.

Example 49 (General procedure (A)) 1H-Benzotriazole-5-carboxylic acid(3-chloro-4-methoxyphenyl)amide

HPLC-MS (Method A): m/z: 303 (M+1); Rt=2.88 min.

Example 50 (General procedure (A)) 1H-Benzotriazole-5-carboxylic acid(4-phenoxyphenyl)amide

HPLC-MS (Method A): m/z: 331 (M+1); Rt=3.62 min.

Example 51 (General procedure (A)) 1H-Benzotriazole-5-carboxylic acid(4-butoxyphenyl)amide

HPLC-MS (Method A): m/z: 311 (M+1); Rt=3.59 min.

Example 52 (General procedure (A)) 1H-Benzotriazole-5-carboxylic acid(3-bromo-4-trifluoromethoxyphenyl)amide

HPLC-MS (Method A): m/z: 402 (M+1); Rt=3.93 min.

Example 53 (General procedure (A)) 1H-Benzotriazole-5-carboxylic acid(3,5-dichloro-4-hydroxyphenyl)amide

HPLC-MS (Method A): m/z: 323 (M+1); Rt=2.57 min.

Example 54 (General procedure (A))4-{[(1H-Benzotriazole-5-carbonyl)amino]methyl}benzoic acid

HPLC-MS (Method A): m/z: 297 (M+1); Rt=1.86 min.

Example 55 (General procedure (A)){4-[(1H-Benzotriazole-5-carbonyl)amino]phenylsulfanyl}acetic acid

HPLC-MS (Method A): m/z: 329 (M+1); Rt=2.34 min.

Example 56 N-(1H-Benzotriazol-5-yl)acetamide

HPLC-MS (Method A): m/z: 177 (M+1); Rt=0.84 min.

Example 57 (General Procedure (A)) 1H-Benzotriazole-5-carboxylic acid4-nitrobenzylamide

The following compound is prepared according to general procedure (N) asdescribed below:

Example 58 (General procedure (N)) 1H-Benzotriazole-5-carboxylic acid4-chlorobenzylamide

HPLC-MS (Method B): m/z: 287 (M+1); Rt=4.40 min.

Example 59 2-[(1H-Benzotriazol-5-ylimino)methyl]-4,6-dichlorophenol

Example 60 Diethyl 2-[(1H-benzotriazol-6-ylamino)methylidene]malonate

Example 61 N1-(1H-Benzotriazol-5-yl)-3-chlorobenzamide

Example 62 N1-(1H-Benzotriazol-5-yl)-3,4,5-trimethoxybenzamide

Example 63N2-(1H-Benzotriazol-5-yl)-3-chlorobenzo[b]thiophene-2-carboxamide

Example 64 6-Bromo-1H-benzotriazole

Example 65 2-[(1H-Benzotriazol-5-ylimino)methyl]-4-bromophenol

General Procedure (B) for Preparation of Compounds of General FormulaI₂:

wherein X, Y, A and R³ are as defined above and A is optionallysubstituted with up to four substituents R⁷, R⁸, R⁹, and R¹⁰ as definedabove.

The chemistry is well known (eg Lohray et al., J. Med. Chem., 1999, 42,2569-81) and is generally performed by reacting a carbonyl compound(aldehyde or ketone) with the heterocyclic ring (egthiazolidine-2,4-dione (X═O; Y═S), rhodanine (X═Y═S) and hydantoin (X═O;Y═NH) in the presence of a base, such as sodium acetate, potassiumacetate, ammonium acetate, piperidinium benzoate or an amine (egpiperidine, triethylamine and the like) in a solvent (eg acetic acid,ethanol, methanol, DMSO, DMF, NMP, toluene, benzene) or in a mixture oftwo or more of these solvents. The reaction is performed at roomtemperature or at elevated temperature, most often at or near theboiling point of the mixture. Optionally, azeotropic removal of theformed water can be done.

This general procedure (B) is further illustrated in the followingexample:

Example 66 General Procedure (B)5-(3-Phenoxybenzylidene)thiazolidine-2,4-dione

A solution of thiazolidine-2,4-dione (90%, 78 mg, 0.6 mmol) and ammoniumacetate (92 mg, 1.2 mmol) in acetic acid (1 mL) was added to3-phenoxybenzaldehyde (52 μL, 0.6 mmol) and the resulting mixture wasshaken at 115° C. for 16 hours. After cooling, the mixture wasconcentrated in vacuo to afford the title compound.

HPLC-MS (Method A): m/z: 298 (M+1); Rt=4.54 min.

The compounds in the following examples were similarly prepared.Optionally, the compounds can be further purified by filtration andwashing with water, ethanol and/or heptane instead of concentration invacuo. Also optionally the compounds can be purified by washing withethanol, water and/or heptane, or by chromatography, such as preparativeHPLC.

Example 67 General Procedure (B)5-(4-Dimethylaminobenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 249 (M+1); Rt=4.90 min

Example 68 General procedure (B)5-Naphthalen-1-ylmethylenethiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 256 (M+1); Rt=4.16 min.

Example 69 General procedure (B) 5-Benzylidene-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 206 (M+1); Rt=4.87 min.

Example 70 General procedure (B)5-(4-Diethylaminobenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 277 (M+1); Rt=4.73 min.

Example 71 General Procedure (B)5-(4-Methoxy-benzylidene)-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 263 (M+1); Rt=4.90 min.

Example 72 General Procedure (B)5-(4-Chloro-benzylidene)-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 240 (M+1); Rt=5.53 min.

Example 73 General Procedure (B)5-(4-Nitro-benzylidene)-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 251 (M+1); Rt=4.87 min.

Example 74 General Procedure (B)5-(4-Hydroxy-3-methoxy-benzylidene)-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 252 (M+1); Rt=4.07 min.

Example 75 General Procedure (B)5-(4-Methylsulfanylbenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 252 (M+1); Rt=5.43 min.

Example 76 General Procedure (B)5-(2-Pentyloxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 292 (M+1); Rt=4.75 min. ¹H NMR (DMSO-d₆):δ=0.90 (3H, t), 1.39 (4H, m), 1.77 (2H, p), 4.08 (2H, t), 7.08 (1H, t),7.14 (1H, d), 7.43 (2H, m), 8.03 (1H, s), 12.6 (1H, bs).

Example 77 General Procedure (B)5-(3-Fluoro-4-methoxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 354 (M+1); Rt=4.97 min.

Example 78 General Procedure (B)5-(4-tert-Butylbenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 262 (M+1); Rt=6.70 min.

Example 79 General Procedure (B)N-[4-2,4-Dioxothiazolidin-5-ylidenemethyl)phenyl]acetamide

HPLC-MS (Method A): m/z: 263 (M+1); Rt=3.90 min.

Example 80 General Procedure (B)5-Biphenyl-4-ylmethylene-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 282 (M+1); Rt=4.52 min.

Example 81 General Procedure (B)5-(4-Phenoxy-benzylidene)-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 298 (M+1); Rt=6.50 min.

Example 82 General Procedure (B)5-(3-Benzyloxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 312 (M+1); Rt=6.37 min.

Example 83 General Procedure (B)5-(3-p-Tolyloxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 312 (M+1); Rt=6.87 min.

Example 84 General Procedure (B)5-Naphthalen-2-ylmethylene-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 256 (M+1); Rt=4.15 min.

Example 85 General Procedure (B)5-Benzo[1,3]dioxol-5-ylmethylenethiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 250 (M+1), Rt=3.18 min.

Example 86 General Procedure (B)5-(4-Chlorobenzylidene)-2-thioxothiazolidin-4-one

HPLC-MS (Method A): m/z: 256 (M+1); Rt=4.51 min.

Example 87 General Procedure (B)5-(4-Dimethylaminobenzylidene)-2-thioxothiazolidin-4-one

HPLC-MS (Method A): m/z: 265 (M+1); Rt=5.66 min.

Example 88 General Procedure (B)5-(4-Nitrobenzylidene)-2-thioxothiazolidin-4-one

HPLC-MS (Method A): m/z: 267 (M+1); Rt=3.94 min.

Example 89 General Procedure (B)5-(4-Methylsulfanylbenzylidene)-2-thioxothiazolidin-4-one

HPLC-MS (Method A): m/z: 268 (M+1); Rt=6.39 min.

Example 90 General Procedure (B)5-(3-Fluoro-4-methoxybenzylidene)-2-thioxothiazolidin-4-one

HPLC-MS (Method A): m/z: 270 (M+1); Rt=5.52 min.

Example 91 General Procedure (B)5-Naphthalen-2-ylmethylene-2-thioxothiazolidin-4-one

HPLC-MS (Method A): m/z: 272 (M+1); Rt=6.75 min.

Example 92 General Procedure (B)5-(4-Diethylaminobenzylidene)-2-thioxothiazolidin-4-one

HPLC-MS (Method A): m/z: 293 (M+1); Rt=5.99 min.

Example 93 General Procedure (B)5-Biphenyl-4-ylmethylene-2-thioxothiazolidin-4-one

HPLC-MS (Method A): m/z: 298 (M+1); Rt=7.03 min.

Example 94 General Procedure (B)5-(3-Phenoxybenzylidene)-2-thioxothiazolidin-4-one

HPLC-MS (Method A): m/z: 314 (M+1); Rt=6.89 min.

Example 95 General Procedure (B)5-(3-Benzyloxybenzylidene)-2-thioxothiazolidin-4-one

HPLC-MS (Method A): m/z: 328 (M+1); Rt=6.95 min.

Example 96 General Procedure (B)5-(4-Benzyloxybenzylidene)-2-thioxothiazolidin-4-one

HPLC-MS (Method A): m/z: 328 (M+1); RT=6.89 min.

Example 97 General Procedure (B)5-Naphthalen-1-ylmethylene-2-thioxothiazolidin-4-one

HPLC-MS (Method A): m/z: 272 (M+1); Rt=6.43 min.

Example 98 General Procedure (B)5-(3-Methoxybenzyl)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 236 (M+1); Rt=3.05 min.

Example 99 General Procedure (D)4-[2-Chloro-4-(2,4-dioxothiazolidin-5-ylidenemethyl)phenoxy]butyric acidethyl ester

HPLC-MS (Method A): m/z: 392 (M+23), Rt=4.32 min.

Example 100 General Procedure (D)4-[2-Bromo-4-(2,4-dioxothiazolidin-5-ylidenemethyl)-phenoxy]-butyricacid

HPLC-MS (Method A): m/z: 410 (M+23); Rt=3.35 min.

Example 101 General Procedure (B)5-(3-Bromobenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 285 (M+1); Rt=4.01 min.

Example 102 General Procedure (B)5-(4-Bromobenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 285 (M+1); Rt=4.05 min.

Example 103 General Procedure (B)5-(3-Chlorobenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 240 (M+1); Rt=3.91 min.

Example 104 General Procedure (B)5-Thiophen-2-ylmethylenethiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 212 (M+1); Rt=3.09 min.

Example 105 General Procedure (B)5-(4-Bromothiophen-2-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 291 (M+1); Rt=3.85 min.

Example 106 General Procedure (B)5-(3,5-Dichlorobenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 274 (M+1); Rt=4.52 min.

Example 107 General Procedure (B)5-(1-Methyl-1H-indol-3-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 259 (M+1); Rt=3.55 min.

Example 108 General Procedure (B)5-(1H-Indol-3-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 245 (M+1); Rt=2.73 min.

Example 109 General Procedure (B)5-Fluoren-9-ylidenethiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 280 (M+1); Rt=4.34 min.

Example 110 General Procedure (B)5-(1-Phenylethylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 220 (M+1); Rt=3.38 min.

Example 111 General Procedure (B)5-[1-(4-Methoxyphenyl)-ethylidene]-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 250 (M+1); Rt=3.55 min.

Example 112 General Procedure (B)5-(1-Naphthalen-2-yl-ethylidene)-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 270 (M+1); Rt=4.30 min.

Example 113 General Procedure (B)5-[1-(4-Bromophenyl)-ethylidene]-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 300 (M+1); Rt=4.18 min.

Example 114 General Procedure (B)5-(2,2-Diphenylethylidene)-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 296 (M+1); Rt=4.49 min.

Example 115 General Procedure (B)5-[1-(3-Methoxyphenyl)-ethylidene]-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 250 (M+1); Rt=3.60 min.

Example 116 General Procedure (B)5-[1-(6-Methoxynaphthalen-2-yl)-ethylidene]-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 300 (M+1); Rt=4.26 min.

Example 117 General Procedure (B)5-[1-(4-Phenoxyphenyl)-ethylidene]-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 312 (M+1); Rt=4.68 min.

Example 118 General Procedure (B)5-[1-(3-Fluoro-4-methoxyphenyl)ethylidene]thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 268 (M+1); Rt=3.58 min.

Example 119 General Procedure (B)5-[1-(3-Bromophenyl)-ethylidene]-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 300 (M+1); Rt=4.13 min.

Example 120 General Procedure (B)5-Anthracen-9-ylmethylenethiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 306 (M+1); Rt=4.64 min.

Example 121 General Procedure (B)5-(2-Methoxynaphthalen-1-ylmethylene)-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 286 (M+1); Rt=4.02 min.

Example 122 General Procedure (B)5-(4-Methoxynaphthalen-1-ylmethylene)-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 286 (M+1); Rt=4.31 min.

Example 123 General Procedure (B)5-(4-Dimethylaminonaphthalen-1-ylmethylene)-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 299 (M+1); Rt=4.22 min.

Example 124 General Procedure (B)5-(4-Methylnaphthalen-1-ylmethylene)-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 270 (M+1); Rt=4.47 min.

Example 125 General Procedure (B)5-Pyridin-2-ylmethylene-thiazolidine-2,4-dione

Example 126 5-Pyridin-2-ylmethyl-thiazolidine-2,4-dione

5-Pyridin-2-ylmethylene-thiazolidine-2,4-dione (5 g) in tetrahydrofuran(300 ml) was added 10% Pd/C (1 g) and the mixture was hydrogenated atambient pressure for 16 hours. More 10% Pd/C (5 g) was added and themixture was hydrogenated at 50 psi for 16 hours. After filtration andevaporation in vacuo, the residue was purified by column chromatographyeluting with a mixture of ethyl acetate and heptane (1:1). This affordedthe title compound (0.8 g, 16%) as a solid.

TLC: R_(f)=0.30 (SiO₂; EtOAc: heptane 1:1)

Example 127 General Procedure (B)5-(1H-Imidazol-4-ylmethylene)-thiazolidine-2,4-dione

Example 128 General Procedure (B)5-(4-Benzyloxy-benzylidene)-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 6.43 min; 99% (2A)

Example 129 General Procedure (B)5-[4-(4-Fluorobenzyloxy)benzylidene]-2-thioxothiazolidin-4-one

Example 130 General Procedure (B)5-(4-Butoxybenzylidene)-2-thioxothiazolidin-4-one

Example 131 General Procedure (B)5-(3-Methoxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 236 (M+1); Rt=4.97 min

Example 132 General Procedure (B)5-(3-Methoxybenzylidene)imidazolidine-2,4-dione

HPLC-MS (Method A): m/z: 219 (M+1); Rt=2.43 min.

Example 133 General Procedure (B)5-(4-Methoxybenzylidene)imidazolidine-2,4-dione

HPLC-MS (Method A): m/z: 219 (M+1); Rt=2.38 min.

Example 134 General Procedure (B)5-(2,3-Dichlorobenzylidene)thiazolidine-2,4-dione

Example 135 General Procedure (B)5-Benzofuran-7-ylmethylenethiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 247 (M+1); Rt=4.57 min.

Example 136 General Procedure (B)5-Benzo[1,3]dioxol-4-ylmethylenethiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 250 (M+1); Rt=4.00 min.

Example 137 General Procedure (B)5-(4-Methoxy-2,3-dimethylbenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 264 (M+1); Rt=5.05 min.

Example 138 General Procedure (B)5-(2-Benzyloxy-3-methoxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 342 (M+1); Rt=5.14 min.

Example 139 General Procedure (B)5-(2-Hydroxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 222 (M+1); Rt=3.67 min.

Example 140 General Procedure (B)5-(2,4-Dichlorobenzylidene)thiazolidine-2,4-dione

¹H-NMR (DMSO-d₆): 7.60 (2H, “s”), 7.78 (1H, s), 7.82 (1H, s).

Example 141 General Procedure (B)5-(2-Chlorobenzylidene)thiazolidine-2,4-dione

¹H-NMR (DMSO-d₆): 7.40 (1H, t), 7.46 (1H, t), 7.57 (1H, d), 7.62 (1H,d), 7.74 (1H, s).

Example 142 General Procedure (B)5-(2-Bromobenzylidene)thiazolidine-2,4-dione

¹H-NMR (DMSO-d₆): 7.33 (1H, t), 7.52 (1H, t), 7.60 (1H, d), 7.71 (1H,s), 7.77 (1H, d).

Example 143 General Procedure (B)5-(2,4-Dimethoxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 266 (M+1) Rt=4.40 min.

Example 144 General Procedure (B)5-(2-Methoxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 236 (M+1); Rt=4.17 min.

Example 145 General Procedure (B)5-(2,6-Difluorobenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 242 (M+1); Rt=4.30 min.

Example 146 General Procedure (B)5-(2,4-Dimethylbenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 234 (M+1); Rt=5.00 min.

Example 147 General Procedure (B)5-(2,4,6-Trimethoxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 296 (M+1); Rt=4.27 min.

Example 148 General Procedure (B)5-(4-Hydroxy-2-methoxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 252 (M+1); Rt=3.64 min.

Example 149 General Procedure (B)5-(4-Hydroxynaphthalen-1-ylmethylene)thiazolidine-2,4-dione

¹H-NMR (DMSO-d₆): δ=7.04 (1H, d), 7.57 (2H, m), 7.67 (1H, t), 8.11 (1H,d), 8.25 (1H, d), 8.39 (1H, s) 11.1 (1H, s), 12.5 (1H, bs). HPLC-MS(Method C): m/z: 272 (M+1); Rt=3.44 min.

Example 150 General Procedure (B)5-(2-Trifluoromethoxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 290 (M+1); Rt=4.94 min.

Example 151 General Procedure (B)5-Biphenyl-2-ylmethylenethiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 282 (M+1); Rt=5.17 min.

Example 152 General Procedure (B)5-(2-Benzyloxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 312 (M+1); Rt=5.40 min.

Example 153 General Procedure (B)5-Adamantan-2-ylidenethiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 250 (M+1); Rt=4.30 min.

Example 154 General Procedure (B)5-[3-(4-Nitrophenyl)allylidene]thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 277 (M+1); Rt=3.63 min.

Example 155 General Procedure (B)5-[3-(2-Methoxyphenyl)allylidene]thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 262 (M+1); Rt=3.81 min.

Example 156 General Procedure (B)5-[3-(4-Methoxyphenyl)allylidene]thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 262 (M+1); Rt=3.67 min.

Example 157 General Procedure (B)5-(4-Hydroxybenzylidene)thiazolidine-2,4-dione

Example 158 General Procedure (B)5-(4-Dimethylaminobenzylidene)pyrimidine-2,4,6-trione

HPLC-MS (Method C): m/z=260 (M+1) Rt=2.16 min.

Example 159 General Procedure (B)5-(9-Ethyl-9H-carbazol-2-ylmethylene)-pyrimidine-2,4,6-trione

HPLC-MS (Method C): m/z=334 (M+1); Rt=3.55 min.

Example 160 General Procedure (B)5-(4-Hexyloxynaphthalen-1-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=356 (M+1); Rt=5.75 min.

Example 161 General Procedure (B)5-(4-Decyloxynaphthalen-1-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=412 (M+1); Rt=6.44 min.

Example 162 General Procedure (B)5-[4-(2-Aminoethoxy)-naphthalen-1-ylmethylene]-thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=315 (M+1); Rt=3.24 min.

Example 163 General Procedure (B)5-(2,4-Dimethyl-9H-carbazol-3-ylmethylene)-pyrimidine-2,4,6-trione

HPLC-MS (Method C): m/z=334 (M+1); Rt=3.14 min.

Example 164 General Procedure (B)4-(4-Hydroxy-3-methoxybenzylidine)hydantoin

Example 165 General Procedure (B) 5-Benzylidenehydantoin

General Procedure (C) for Preparation of Compounds of General FormulaI₂:

wherein X, Y, A, and R³ are as defined above and A is optionallysubstituted with up to four substituents R⁷, R⁸, R⁹, and R¹⁰ as definedabove.

This general procedure (C) is quite similar to general procedure (B) andis further illustrated in the following example:

Example 166 General Procedure (C)5-(3,4-Dibromobenzylidene)thiazolidine-2,4-dione

A mixture of thiazolidine-2,4-dione (90%, 65 mg, 0.5 mmol),3,4-dibromobenzaldehyde (132 mg, 0.5 mmol), and piperidine (247 μL, 2.5mmol) was shaken in acetic acid (2 mL) at 110° C. for 16 hours. Aftercooling, the mixture was concentrated to dryness in vacuo.

The resulting crude product was shaken with water, centrifuged, and thesupernatant was discarded. Subsequently the residue was shaken withethanol, centrifuged, the supernatant was discarded and the residue wasfurther evaporated to dryness to afford the title compound.

¹H NMR (Acetone-d₆): δ_(H) 7.99 (d, 1H), 7.90 (d, 1H), 7.70 (s, 1H),7.54 (d, 1H); HPLC-MS (Method A): m/z: 364 (M+1); Rt=4.31 min.

The compounds in the following examples were similarly prepared.Optionally, the compounds can be further purified by filtration andwashing with water instead of concentration in vacuo. Also optionallythe compounds can be purified by washing with ethanol, water and/orheptane, or by preparative HPLC.

Example 167 General Procedure (C)5-(4-Hydroxy-3-iodo-5-methoxybenzylidene)thiazolidine-2,4-dione

Mp=256° C.; ¹H NMR (DMSO-d₆) δ=12.5 (s,broad, 1H), 10.5 (s,broad, 1H),7.69 (s, 1H), 7.51 (d, 1H), 7.19 (d, 1H)3.88 (s,3H), ¹³C NMR (DMSO-d₆)δ_(C)=168.0, 167.7, 149.0, 147.4, 133.0, 131.2, 126.7, 121.2, 113.5,85.5, 56.5; HPLC-MS (Method A): m/z: 378 (M+1); Rt=3.21 min.

Example 168 General Procedure (C)5-(4-Hydroxy-2,6-dimethylbenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 250 (M+1); Rt.=2.45 min.

Example 169 General Procedure (C)4-[5-Bromo-6-(2,4-dioxothiazolidin-5-ylidenemethyl)-naphthalen-2-yloxymethyl]-benzoicacid

HPLC-MS (Method C): m/z: 506 (M+23); Rt.=4.27 min.

Example 170 General Procedure (C)5-(4-Bromo-2,6-dichlorobenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 354 (M+1); Rt.=4.36 min.

Example 171 General Procedure (C)5-(6-Hydroxy-2-naphthylmethylene)thiazolidine-2,4-dione

Mp 310-314° C., ¹H NMR (DMSO-d₆): δ_(H)=12.5 (s,broad, 1H), 8.06(d, 1H),7.90-7.78(m,2H),7.86 (s, 1H), 7.58 (dd, 1H),7.20 7.12 (m,2H). ¹³C NMR(DMSO-d₆): δ_(C)=166.2, 165.8, 155.4, 133.3, 130.1, 129.1, 128.6, 125.4,125.3, 125.1, 124.3, 120.0, 117.8, 106.8; HPLC-MS (Method A): m/z: 272(M+1); Rt=3.12 min.

Preparation of the Starting Material, 6-hydroxy-2-naphtalenecarbaldehyde

6-Cyano-2-naphthalenecarbaldehyde (1.0 g, 5.9 mmol) was dissolved in dryhexane (15 mL) under nitrogen. The solution was cooled to −60° C. and asolution of diisobutyl aluminium hydride (DIBAH) (15 mL, 1M in hexane)was added dropwise. After the addition, the solution was left at roomtemperature overnight. Saturated ammonium chloride solution (20 mL) wasadded and the mixture was stirred at room temperature for 20 min,subsequently aqueous H₂SO₄ (10% solution, 15 mL) was added followed bywater until all salt was dissolved. The resulting solution was extractedwith ethyl acetate (3×), the combined organic phases were dried withMgSO₄, evaporated to dryness to afford 0.89 g of6-hydroxy-2-naphtalenecarbaldehyde.

Mp.: 153.5-156.5° C.; HPLC-MS (Method A): m/z: 173 (M+1); Rt=2.67 min;¹H NMR (DMSO-d₆): δ_(H)=10.32(s, 1H), 8.95 (d, 1H), 10.02 (s, 1H), 8.42(s,broad, 1H), 8.01 (d, 1H), 7.82-7.78 (m,2H), 7.23-7.18 (m,2H).

Alternative Preparation of 6-hydroxy-2-naphtalenecarbaldehyde

To a stirred cooled mixture of 6-bromo-2-hydroxynaphthalene (25.3 g,0.113 mol) in THF (600 mL) at −78° C. was added n-BuLi (2.5 M, 100 mL,0.250 mol) dropwise. The mixture turned yellow and the temperature roseto −64° C. After ca 5 min a suspension appeared. After addition, themixture was maintained at −78° C. After 20 minutes, a solution of DMF(28.9 mL, 0.373 mol) in THF (100 mL) was added over 20 minutes. Afteraddition, the mixture was allowed to warm slowly to room temperature.After 1 hour, the mixture was poured in ice/water (200 mL). To themixture citric acid was added to a pH of 5. The mixture was stirred for0.5 hour. Ethyl acetate (200 mL) was added and the organic layer wasseparated and washed with brine (100 mL), dried over Na₂SO₄ andconcentrated. To the residue was added heptane with 20% ethyl acetate(ca 50 mL) and the mixture was stirred for 1 hour. The mixture wasfiltered and the solid was washed with ethyl acetate and dried in vacuoto afford 16 g of the title compound.

Example 172 General Procedure (C)5-(3-Iodo-4-methoxybenzylidene)thiazolidiene-2,4-dione

¹H NMR (DMSO-d₆): δ_(H) 12.55 (s,broad, 1H), 8.02 (d, 1H), 7.72 (s, 1H),7.61 (d, 1H)7.18(d, 1H), 3.88 (s,3H); ¹³C NMR (DMSO-d₆): δ_(C) 168.1,167.7, 159.8, 141.5, 132.0, 130.8, 128.0, 122.1, 112.5, 87.5, 57.3.HPLC-MS (Method A): m/z: 362 (M+1); Rt=4.08 min.

Preparation of the Starting Material, 3-iodo-4-methoxybenzaldehyde

4-Methoxybenzaldehyde (0.5 g, 3.67 mmol) and silver trifluoroacetate(0.92 g, 4.19 mmol) were mixed in dichloromethane (25 mL). Iodine (1.19g, 4.7 mmol) was added in small portions and the mixture was stirredovernight at room temperature under nitrogen. The mixture wassubsequently filtered and the residue washed with DCM. The combinedfiltrates were treated with an acqueous sodium thiosulfate solution (1M) until the colour disappeared. Subsequent extraction withdichloromethane (3×20 mL) followed by drying with MgSO₄ and evaporationin vacuo afforded 0.94 g of 3-iodo-4-methoxybenzaldehyde.

Mp 104-107° C.; HPLC-MS (Method A): m/z:263 (M+1); Rt=3.56 min.;¹H NMR(CDCl₃): δ_(H)=8.80 (s, 1H), 8.31 (d, 1H), 7.85 (dd, 1H) 6.92 (d, 1H),3.99 (s, 3H).

Example 173 General Procedure (C)5-(1-Bromonaphthalen-2-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z:=336 (M+1); Rt=4.46 min.

Example 174 General Procedure (C)1-[5-(2,4-Dioxothiazolidin-5-ylidenemethyl)thiazol-2-yl]piperidine-4-carboxylicacid ethyl ester

¹H NMR (DMSO-d₆): δ_(H)=7.88 (s, 1H), 7.78 (s, 1H), 4.10 (q,2H), 4.0-3.8(m,2H), 3.40-3.18 (m,2H), 2.75-2.60 (m, 1H), 2.04-1.88 (m,2H), 1.73-1.49(m,2H), 1.08 (t,3H); HPLC-MS (Method A): m/z: 368 (M+1); Rt=3.41 min.

Example 175 General Procedure (C)5-(2-Phenyl-[1,2,3]triazol-4-ylmethylene)thiazolidine-2,4-dione

¹H NMR (DMSO-d₆): δ_(H)=12.6 (s,broad, 1H), 8.46 (s, 1H), 8.08 (dd,2H),7.82 (s, 1H), 7.70-7.45 (m, 3H). HPLC-MS (Method A): m/z: 273 (M+1);Rt=3.76 min.

Example 176 General Procedure (C)5-(Quinolin-4-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 257 (M+1); Rt=2.40 min.

Example 177 General Procedure (C)5-(6-Methylpyridin-2-ylmethylene)thiazolidine-2,4-dione

¹H NMR (DMSO-d₆): δ_(H)=12.35 (s,broad, 1H), 7.82 (t, 1H), 7.78 (s, 1H),7.65 (d, 1H), 7.18 (d, 1H), 2.52 (s,3 H); HPLC-MS (Method A): m/z: 221(M+1); Rt=3.03 min.

Example 178 General Procedure (C)5-(2,4-dioxothiazolidin-5-ylidenemethyl)-furan-2-ylmethylacetate

¹H NMR (DMSO-d₆): δ_(H)=12.46 (s,broad, 1H), 7.58 (s, 1H), 7.05 (d, 1H),6.74 (s, 1H), 5.13 (s,2H), 2.10 (s,3H). HPLC-MS (Method A): m/z: 208(M-CH₃COO); Rt=2.67 min.

Example 179 General Procedure (C)5-(2,4-Dioxothiazolidin-5-ylidenemethyl)furan-2-sulfonic acid

HPLC-MS (Method A): m/z:276 (M+1); Rt=0.98 min.

Example 180 General Procedure (C)5-(5-Benzyloxy-1H-pyrrolo[2,3-c]pyridin-3-ylmethylene)-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 352 (M+1); Rt=3.01 min.

Example 181 General Procedure (C)

5-(Quinolin-2-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 257 (M+1); Rt=3.40 min.

Example 182 General Procedure (C)5-(2,4-Dioxothiazolidin-5-ylidenemethyl)thiophene-2-carboxylic acid

HPLC-MS (Method A): m/z: 256 (M+1); Rt=1.96 min.

Example 183 General Procedure (C)5-(2-Phenyl-1H-imidazol-4-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 272 (M+1); Rt=2.89 min.

Example 184 General Procedure (C)5-(4-Imidazol-1-yl-benzylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 272 (M+1); Rt=1.38 min.

Example 185 General Procedure (C)5-(9-Ethyl-9H-carbazol-3-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 323 (M+1); Rt=4.52 min.

Example 186 General Procedure (C)5-(1,4-Dimethyl-9H-carbazol-3-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 323 (M+1); Rt=4.35 min.

Example 187 General Procedure (C)5-(2-Methyl-1H-indol-3-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 259 (M+1); Rt=3.24 min.

Example 188 General Procedure (C)5-(2-Ethylindol-3-ylmethylene)thiazolidine-2,4-dione

2-Methylindole (1.0 g, 7.6 mmol) dissolved in diethyl ether (100 mL)under nitrogen was treated with n-Butyl lithium (2 M in pentane, 22.8mmol) and potassium tert-butoxide (15.2 mmol) with stirring at RT for 30min. The temperature was lowered to −70 C and methyl Iodide (15.2 mmol)was added and the resulting mixture was stirred at −70 for 2 h. Then 5drops of water was added and the mixture allowed to warm up to RT.Subsequently, the mixture was poured into water (300 mL), pH wasadjusted to 6 by means of 1N hydrochloric acid and the mixture wasextracted with diethyl ether. The organic phase was dried with Na₂SO₄and evaporated to dryness. The residue was purified by columnchromatography on silica gel using heptane/ether( 4/1) as eluent. Thisafforded 720 mg (69%) of 2-ethylindole.

¹H NMR (DMSO-d₆): δ=10.85 (1H,s); 7.39 (1H,d); 7.25 (1H,d); 6.98(1H,t);6.90(1H,t); 6.10 (1H,s); 2.71 (2H,q); 1.28 (3H,t).

2-Ethylindole (0.5 g, 3.4 mmol) dissolved in DMF (2 mL) was added to acold (0° C.) premixed (30 minutes) mixture of DMF (1.15 mL) andphosphorous oxychloride(0.64 g, 4.16 mmol). After addition of2-ethylindole, the mixture was heated to 40° C. for 1 h, water (5 mL)was added and the pH adjusted to 5 by means of 1 N sodium hydroxide.Themixture was subsequently extracted with diethyl ether, the organic phaseisolated, dried with MgSO₄ and evaporated to dryness affording2-ethylindole-3-carbaldehyde (300 mg).

HPLC-MS (Method C): m/z:174 (M+1); Rt.=2.47 min.

2-Ethylindole-3-carbaldehyde (170 mg) was treated withthiazolidine-2,4-dione using the general procedure (C) to afford thetitle compound (50 mg).

HPLC-MS (Method C):m/z: 273 (M+1); Rt.=3.26 min.

Example 189 General Procedure (C)5-[2-(4-Bromophenylsulfanyl)-1-methyl-1H-indol-3-ylmethylene]thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 447 (M+1); Rt=5.25 min.

Example 190 General Procedure (C)5-[2-(2,4-Dichlorobenzyloxy)-naphthalen-1-ylmethylene]thiazolidine-2,4-dione

HPLC-MS (Method A): (anyone 1) m/z: 430 (M+1); Rt=5.47 min.

Example 191 General Procedure (C)5-{4-[3-(4-Bromophenyl)-3-oxopropenyl]-benzylidene}thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 416 (M+1); Rt=5.02 min.

Example 192 General Procedure (C)5-(4-Pyridin-2-ylbenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 283 (M+1), Rt=2.97 min.

Example 193 General Procedure (C)5-(3,4-Bisbenzyloxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 418 (M+1); Rt=5.13 min.

Example 194 General Procedure (C)5-[4-(4-Nitrobenzyloxy)-benzylidene]thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 357 (M+1); Rt=4.45 min.

Example 195 General Procedure (C)5-(2-Phenyl-1H-indol-3-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 321 (M+1); Rt=3.93 min.

Example 196 General Procedure (C)5-(5-Benzyloxy-1H-indol-3-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 351 (M+1); Rt=4.18 min.

Example 197 General Procedure (C)5-(4-Hydroxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 222 (M+1); Rt=2.42 min.

Example 198 General Procedure (C)5-(1-Methyl-1H-indol-2-ylmethylene)thiazolidine-2,4-dione

¹H NMR (DMSO-d₆): δ_(H)=12.60 (s,broad, 1H), 7.85 (s, 1H), 7.68 (dd,1H), 7.55 (dd, 1H), 7.38 (dt, 1H), 7.11 (dt, 1H) 6.84 (s, 1H), 3.88(s,3H); HPLC-MS (Method A): m/z: 259 (M+1); Rt=4.00 min.

Example 199 General Procedure (C)5-(5-Nitro-1H-indol-3-ylmethylene)thiazolidine-2,4-dione

Mp 330-333° C., ¹H NMR (DMSO-d₆): δ_(H)=12.62 (s,broad, 1H), 8.95 (d,1H), 8.20 (s, 1H), 8.12 (dd, 1H), 7.98 (s,broad, 1H), 7.68 (d, 1H);HPLC-MS (Method A): m/z: 290 (M+1); Rt=3.18 min.

Example 200 General Procedure (C)5-(6-Methoxynaphthalen-2-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 286 (M+1); Rt=4.27 min.

Example 201 General Procedure (C)5-(3-Bromo-4-methoxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 314 (M+1), Rt=3.96 min.

Example 202 General Procedure (C)3-{(2-Cyanoethyl)-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)phenyl]amino}propionitrile

HPLC-MS (Method A): m/z: 327 (M+1); Rt=2.90 min.

Example 203 General Procedure (C)3-(2,4-Dioxothiazolidin-5-ylidenemethyl)indole-6-carboxylic acid methylester

HPLC-MS (Method A): m/z: 303 (M+1); Rt=3.22-3-90 min.

Example 204 3-(2,4-Dioxothiazolidin-5-ylidenemethyl)indole-6-carboxylicacid pentyl ester

3-(2,4-Dioxothiazolidin-5-ylidenemethyl)indole-6-carboxylic acid methylester (example 203, 59 mg; 0.195 mmol) was stirred in pentanol (20 mL)at 145° C. for 16 hours. The mixture was evaporated to dryness affordingthe title compound (69 mg).

HPLC-MS (Method C): m/z: 359 (M+1); Rt.=4.25 min.

Example 205 General Procedure (C)3-(2,4-Dioxothiazolidin-5-ylidenemethyl)indole-7-carboxylic acid

HPLC-MS (Method A): m/z: 289 (M+1); Rt=2.67 min.

Example 206 General Procedure (C)5-(1-Benzylindol-3-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 335 (M+1); Rt=4.55 min.

Example 207 General Procedure (C)5-(1-Benzenesulfonylindol-3-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z:=385 (M+1); Rt=4.59 min.

Example 208 General Procedure (C)5-(4-[1,2,3]Thiadiazol-4-ylbenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 290 (M+1); Rt=3.45 min.

Example 209 General Procedure (C)5-[4-(4-Nitrobenzyloxy)-benzylidene]thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 357 (M+1); Rt=4.42 min.

Example 210 General Procedure (C)3-(2,4-Dioxothiazolidin-5-ylidenemethyl)indole-1-carboxylic acid ethylester

HPLC-MS (Method A): m/z: 317 (M+1); Rt=4.35 min.

Example 211 General Procedure (C)5-[2-(4-Pentylbenzoyl)-benzofuran-5-ylmethylene]thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 420 (M+1); Rt=5.92 min.

Example 212 General Procedure (C)5-[1-(2-Fluorobenzyl)-4-nitroindol-3-ylmethylene]thiazolidine-2,4-dione

HPLC-MS (Method A): (Anyone 1) m/z: 398 (M+1); Rt=4.42 min.

Example 213 General Procedure (C)5-(4-Benzyloxyindol-3-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 351 (M+1); Rt=3.95 min.

Example 214 General Procedure (C)5-(4-Isobutylbenzylidene)-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 262 (M+1); Rt=4.97 min.

Example 215 General Procedure (C) Trifluoromethanesulfonic acid4-(2,4-dioxothiazolidin-5-ylidenemethyl)naphthalen-1-yl ester

HPLC-MS (Method A): m/z: 404 (M+1); Rt=4.96 min.

Preparation of Starting Material:

4-Hydroxy-1-naphthaldehyde (10 g, 58 mmol) was dissolved in pyridin (50ml) and the mixture was cooled to 0-5° C. With stirring,trifluoromethanesulfonic acid anhydride (11.7 ml, 70 mmol) was addeddrop-wise. After addition was complete, the mixture was allowed to warmup to room temperature, and diethyl ether (200 ml) was added. Themixture was washed with water (2×250 ml), hydrochloric acid (3N, 200ml), and saturated aqueous sodium chloride (100 ml). After drying(MgSO4), filtration and concentration in vacuo, the residue was purifiedby column chromatography on silica gel eluting with a mixture of ethylacetate and heptane (1:4). This afforded 8.35 g (47%)trifluoromethanesulfonic acid 4-formylnaphthalen-1-yl ester, mp 44-46.6°C.

Example 216 General Procedure (C)5-(4-Nitroindol-3-ylmethylene)-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 290 (M+1); Rt=3.14 min.

Example 217 General Procedure (C)5-(3,5-Dibromo-4-hydroxy-benzylidene)thiazolidine-2,4-dione

¹H NMR (DMSO-d₆): δ_(H)=12.65 (broad, 1H), 10.85 (broad, 1H), 7.78(s,2H), 7.70 (s, 1H); HPLC-MS (Method A): m/z: 380 (M+1); Rt=3.56 min.

Example 218 General Procedure (C)

HPLC-MS (Method A): m/z: 385 (M+1); Rt=5.08 min.

General Procedure for Preparation of Starting Materials for Examples218-221:

Indole-3-carbaldehyde (3.8 g, 26 mmol) was stirred with potassiumhydroxide (1.7 g) in acetone (200 mL) at RT until a solution wasobtained indicating full conversion to the indole potassium salt.Subsequently the solution was evaporated to dryness in vacuo. Theresidue was dissolved in acetone to give a solution containing 2.6mmol/20 mL.

20 mL portions of this solution were mixed with equimolar amounts ofarylmethylbromides in acetone (10 mL). The mixtures were stirred at RTfor 4 days and subsequently evaporated to dryness and checked byHPLC-MS. The crude products, 1-benzylated indole-3-carbaldehydes, wereused for the reaction with thiazolidine-2,4-dione using the generalprocedure C.

Example 219 General Procedure (C)4-[3-(2,4-Dioxothiazolidin-5-ylidenemethyl)indol-1-ylmethyl]benzoic acidmethyl ester

HPLC-MS (Method A): m/z: 393 (M+1); Rt=4.60 min.

Example 220 General Procedure (C)5-[1-(9,10-Dioxo-9,10-dihydroanthracen-2-ylmethyl)-1H-indol-3-ylmethylene]thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 465 (M+1); Rt=5.02 min.

Example 221 General Procedure (C)4′-[3-(2,4-Dioxothiazolidin-5-ylidenemethyl)indol-1-ylmethyl]biphenyl-2-carbonitrile

HPLC-MS (Method A): m/z: 458 (M+23); Rt=4.81 min.

Example 222 General Procedure (C)3-[3-(2,4-Dioxothiazolidin-5-ylidenemethyl)-2-methylindol-1-ylmethyl]benzonitrile

2-Methylindole-3-carbaldehyde (200 mg, 1.26 mmol) was added to a slurryof 3-bromomethylbenzenecarbonitrile (1.26 mmol) followed by sodiumhydride, 60%, (1.26 mmol) in DMF (2 mL). The mixture was shaken for 16hours, evaporated to dryness and washed with water and ethanol. Theresidue was treated with thiazolidine-2,4-dione following the generalprocedure C to afford the title compound (100 mg).

HPLC-MS (Method C): m/z: 374 (M+1); Rt.=3.95 min.

Example 223 General Procedure (C)5-(1-Benzyl-2-methylindol-3-ylmethylene)thiazolidine-2,4-dione

This compound was prepared in analogy with the compound described inexample 222 from benzyl bromide and 2-methylindole-3-carbaldehyde,followed by reaction with thiazolidine-2,4-dione resulting in 50 mg ofthe title compound.

HPLC-MS (Method C): m/z: 349 (M+1); Rt.=4.19 min.

Example 2244-[3-(2,4-Dioxothiazolidin-5-ylidenemethyl)-2-methylindol-1-ylmethyl]benzoicacid methyl ester

This compound was prepared in analogy with the compound described inexample 222 from 4-(bromomethyl)benzoic acid methyl ester and2-methylindole-3-carbaldehyde, followed by reaction withthiazolidine-2,4-dione.

HPLC-MS (Method C): m/z: 407 (M+1); Rt.=4.19 min.

Example 225 General Procedure (C)5-(2-Chloro-1-methyl-1H-indol-3-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 293 (M+1); Rt=4.10 min.

Example 226 General Procedure (C)5-(4-Hydroxy-3,5-diiodo-benzylidene)-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 474 (M+1); Rt=6.61 min.

Example 227 General Procedure (C)5-(4-Hydroxy-3-iodobenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 348 (M+1); Rt.=3.13 min ¹H-NMR: (DMSO-d₆): 11.5(1H,broad); 7.95(1H,d); 7.65(1H,s); 7.45 (1H,dd); 7.01(1H,dd); 3.4(1H,broad).

Example 228 General Procedure (C)5-(2,3,6-Trichlorobenzylidene)thiazolidine-2,4-dione

H PLC-MS (Method C): m/z: 309 (M+1); Rt.=4.07 min

Example 229 General Procedure (C)5-(2,6-Dichlorobenzylidene)thiazolidine-2,4-dione

Mp. 152-154° C. HPLC-MS (Method C): m/z: 274 (M+1), Rt.=3.70 min ¹H-NMR:(DMSO-d₆): 12.8 (1H, broad); 7.72 (1H,s); 7.60 (2H,d); 7.50 (1H,t).

Example 230 General Procedure (C)5-[1-(2,6-Dichloro-4-trifluoromethylphenyl)-2,5-dimethyl-1H-pyrrol-3-ylmethylene]thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 436 (M+1); Rt. 4.81 min

Example 231 General Procedure (C)5-[1-(3,5-Dichlorophenyl)-5-(4-methanesulfonylphenyl)-2-methyl-1H-pyrrol-3-ylmethylene]-thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 508 (M+1); Rt.=4.31 min

Example 232 General Procedure (C)5-[1-(2,5-Dimethoxyphenyl)-5-(4-methanesulfonylphenyl)-2-methyl-1H-pyrrol-3-ylmethylene]-thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 499 (M+1); Rt.=3.70 min

Example 233 General Procedure (C)4-[3-(2,4-Dioxothiazolidin-5-ylidenemethyl)-2,5-dimethylpyrrol-1-yl]benzoicacid

HPLC-MS (Method C): m/z:342 (M+1); Rt.=3.19 min

Example 234 General Procedure (C)5-(4-Hydroxy-2,6-dimethoxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z:282( M+1); Rt.=2.56, mp=331-333° C.

Example 235 General Procedure (C)5-(2,6-Dimethylbenzylidene)thiazolidine-2,4-dione

M.p: 104-105° C. HPLC-MS (Method C): m/z: 234 (M+1); Rt.=3.58 min,

Example 236 General Procedure (C)5-(2,6-Dimethoxybenzylidene)thiazolidine-2,4-dione

Mp: 241-242° C. HPLC-MS (Method C): m/z: 266 (M+1); Rt.=3.25 min;

Example 237 General Procedure (C)5-[4-(2-Fluoro-6-nitrobenzyloxy)-2,6-dimethoxybenzylidene]thiazolidine-2,4-dione

Mp: 255-256° C. HPLC-MS (Method C): m/z: 435 (M+1), Rt 4.13 min,

Example 238 General Procedure (C)5-Benzofuran-2-ylmethylenethiazolidine-2,4-dione

HPLC-MS (Method C): m/z:246 (M+1); Rt.=3.65 min, mp=265-266° C.

Example 239 General Procedure (C)5-[3-(4-Dimethylaminophenyl)allylidene]thiazolidine-2,4-dione

HPLC-MS (Method C): m/z:276(M+1); Rt.=3.63, mp=259-263° C. ¹H-NMR:(DMSO-d₆) δ=12.3 (1H,broad); 7.46 (2H,d); 7.39 (1H,d); 7.11 (1H,d); 6.69(2H,d); 6.59 (1H, dd); 2.98 (3H,s).

Example 240 General Procedure (C)5-(2-Methyl-3-phenylallylidene)thiazolidine-2,4-dione

Mp: 203-210° C. HPLC-MS (Method C): m/z: 246 (M+1); Rt=3.79 min.

Example 241 General Procedure (C)5-(2-Chloro-3-phenylallylidene)thiazolidine-2,4-dione

Mp: 251-254° C. HPLC-MS (Method C): m/z: 266 (M+1; Rt=3.90 min

Example 242 General Procedure (C)5-(2-Oxo-1,2-dihydroquinolin-3-ylmethylene)thiazolidine-2,4-dione

Mp: 338-347° C. HPLC-MS (Method C): m/z: 273 (M+1); Rt.=2.59 min.

Example 243 General Procedure (C)5-(2,4,6-Tribromo-3-hydroxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 459 (M+1);Rt.=3.65 min.

Example 244 General Procedure (C)5-(5-Bromo-2-methylindol-3-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 339 (M+1); Rt=3.37 min.

Example 245 General Procedure (C)5-(7-Bromo-2-methylindol-3-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 319 (M+1); Rt=3.48 min.

Example 246 General Procedure (C)5-(6-Bromoindol-3-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 325 (M+1); Rt=3.54 min.

Example 247 General Procedure (C)5-(8-Methyl-2-oxo-1,2-dihydroquinolin-3-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 287 (M+1); Rt=2.86 min.

Example 248 General Procedure (C)5-(6-Methoxy-2-oxo-1,2-dihydroquinolin-3-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 303 (M+1); Rt=2.65 min.

Example 249 General Procedure (C)5-Quinolin-3-ylmethylenethiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 257 (M+1); Rt=2.77 min.

Example 250 General Procedure (C)5-(8-Hydroxyquinolin-2-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 273 (M+1); Rt=3.44 min.

Example 251 General Procedure (C)5-Quinolin-8-ylmethylenethiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 257 (M+1); Rt=3.15 min.

Example 252 General Procedure (C)5-(1-Bromo-6-methoxynaphthalen-2-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 366 (M+1); Rt=4.44 min.

Example 253 General Procedure (C)5-(6-Methyl-2-oxo-1,2-dihydroquinolin-3-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 287 (M+1); Rt.=2.89 min.

Example 254 General Procedure (D)5-(2,6-Dichloro-4-dibenzylaminobenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 469 (M+1); Rt=5.35 min.

Example 255 General Procedure (C)7-(2,4-Dioxothiazolidin-5-ylidenemethyl)-4-methoxybenzofuran-2-carboxyicacid

HPLC-MS (Method C): m/z: 320 (M+1); Rt=2.71 min.

Preparation of the Intermediate,7-formyl-4-methoxybenzofuran-2-carboxylic acid

A mixture of 2-hydroxy-6-methoxybenzaldehyde (6.4 g, 42 mmol), ethylbromoacetate (14.2 mL, 128 mmol) and potassium carbonate (26 g, 185mmol) was heated to 130° C. After 3 h the mixture was cooled to roomtemperature and acetone (100 mL) was added, the mixture was subsequentlyfiltered and concentrated in vacuo. The residue was purified by columnchromatography on silica gel eluting with a mixture of ethyl acetate andheptane (1:4). This afforded 7.5 g (55%) of ethyl4-methoxybenzofuran-2-carboxylate.

A solution of ethyl 4-methoxybenzofuran-2-carboxylate (6.9 g, 31.3 mmol)in dichloromethane (70 ml) was cooled to 0° C. and a solution oftitanium tetrachloride (13.08 g, 69 mmol) was added drop wise. After 10minutes dichloromethoxymethane (3.958 g, 34 mmol) was added over 10minutes. After addition, the mixture was warmed to room temperature for18 hours and the mixture poured into hydrochloric acid (2N, 100 mL). Themixture was stirred for 0.5 hour and then extracted with a mixture ofethyl acetate and toluene (1:1). The organic phase was dried over Na₂SO₄and concentrated in vacuo. The residue was purified by columnchromatography on silica gel eluting with a mixture of ethyl acetate andheptane (1:4). This afforded 5.8 g (80%) of ethyl7-formyl-4-methoxybenzofuran-2-carboxylate.

7-formyl4-methoxybenzofuran-2-carboxylate (5.0 g, 21.5 mmol) and sodiumcarbonate (43 mmol) in water (100 mL) was refluxed until a clearsolution appeared (about 0.5 hour). The solution was filtered andacidified to pH=1 with hydrochloric acid (2 N), the resulting productwas filtered off and washed with ethyl acetate and ethanol and dried toafford 3.5 g (74%) of 7-formyl-4-methoxybenzofuran-2-carboxylic acid asa solid.

¹H NMR (DMSO-d₆): δ=10.20 (s, 1H); 8.07 (d, 1H); 7.70 (s, 1H); 7.17 (d,1H); 4.08 (s, 3H).

Example 256 General Procedure (C)5-(4-Methoxybenzofuran-7-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 267 (M+1); Rt=3.30 min.

Preparation of the Intermediate, 4-methoxybenzofuran-7-carbaldehyde

A mixture of 7-formyl-4-methoxybenzofuran-2-carboxylic acid (3.0 g, 13.6mmol) and Cu (0.6 g, 9.44 mmol) in quinoline (6 mL) was refluxed. After0.5 h the mixture was cooled to room temperature and water (100 mL) andhydrochloric acid (10 N, 20 mL) were added. The mixture was extractedwith a mixture of ethyl acetate and toluene (1:1), filtered throughcelite and the organic layer separated and washed with a sodiumcarbonate solution, dried over Na₂SO₄ and concentrated in vacuo toafford 1.5 g crude product. Column chromatography SiO₂,EtOAc/heptanes=1/4 gave 1.1 g (46%) of4-methoxybenzofuran-7-carbaldehyde as a solid.

¹H NMR (CDCl₃): δ: 10.30 (s, 1H); 7.85 (d, 1H); 7.75 (d, 1H); 6.98 (d,1H); 6.87 (d, 1H); 4.10 (s,3H). HPLC-MS (Method C):m/z: 177 (M+1);Rt.=7.65 min.

Example 257 General Procedure (C)5-(4-Hydroxybenzofuran-7-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z:=262 (M+1); Rt 2.45 min.

Preparation of the Intermediate, 4-hydroxybenzofuran-7-carbaldehyde

A mixture of 4-methoxybenzofuran-7-carbaldehyde (1.6 g, 9.1 mmol) andpyridine hydrochloride (4.8 g, 41.7 mmol) in quinoline (8 mL) wasrefluxed. After 8 h the mixture was cooled to room temperature andpoured into water (100 mL) and hydrochloric acid (2 N) was added topH=2. The mixture was extracted with a mixture of ethyl acetate andtoluene (1:1), washed with a sodium carbonate solution, dried withNa₂SO₄ and concentrated in vacuo to afford 0.8 g crude product. This waspurified by column chromatography on silica gel, eluting with a mixtureof ethyl acetate and heptane (1:3). This afforded 250 mg of4-hydroxybenzofuran-7-carbaldehyde as a solid.

¹H NMR (DMSO-d₆): δ=11.35 (s, broad, 1H); 10.15 (s, 1H); 8.05 (d, 1H);7.75 (d, 1H); 7.10 (d, 1H); 6.83 (d, 1H). HPLC-MS (Method C): m/z: 163(M+1); Rt.=6.36 min.

Example 258 General Procedure (C)5-(5-Bromo-2,3-dihydrobenzofuran-7-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 328 (M+1); Rt=3.66 min.

Preparation of the Intermediate,5-bromo-2,3-dihydrobenzofuran-7-carbaldehyde

To a cooled (15° C.) stirred mixture dihydrobenzofuran (50.9 g, 0.424mol) in acetic acid (500 mL), a solution of bromine (65.5 mL, 1.27 mol)in acetic acid (200 mL) was added drop wise over 1 hour. After stirringfor 18 hours, a mixture of Na₂S₂O₅ (150 g) in water (250 mL) was addedcarefully, and the mixture was concentrated in vacuo. Water (200 mL) wasadded and the mixture was extracted with ethyl acetate containing 10%heptane, dried over Na₂SO₄ and concentrated in vacuo to give crude5,7-dibromo-2,3-dihydrobenzofuran which was used as such for thefollowing reaction steps. To a cooled solution (−78° C.) of crude5,7-dibromo-2,3-dihydrobenzofuran (50.7 g, 0.182 mol) in THF (375 mL) asolution of n-BuLi (2.5 M, 80 mL, 0.200 mol) in hexane was added. Afteraddition, the mixture was stirred for 20 min. DMF (16 mL) was then addeddrop wise at −78° C. After addition, the mixture was stirred at roomtemperature for 3 h and then the mixture was poured into a mixture ofice water, (500 mL) and hydrochloric acid (10 N, 40 mL) and extractedwith toluene, dried over Na₂SO₄ and concentrated in vacuo. Columnchromatography on silica gel eluting with a mixture of ethyl acetate andheptane (1:4) afforede 23 g of5-bromo-2,3-dihydrobenzofuran-7-carbaldehyde as a solid.

¹H NMR (CDCl₃): δ 10.18 (s, 1H); 7.75 (d, 1H);7.55 (d, 1H); 4.80 (t,2H);3.28 (t,2).

Example 259 General Procedure (C)5-(4-Cyclohexylbenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 288 (M+1); Rt=5.03 min.

Preparation of the Intermediate, 4-cyclohexylbenzaldehyde

This compound was synthesized according to a modified literatureprocedure (J. Org. Chem., 37, No.24, (1972), 3972-3973).

Cyclohexylbenzene (112.5 g, 0.702 mol) and hexamethylenetetramine (99.3g, 0.708 mol) were mixed in TFA (375 mL). The mixture was stirred undernitrogen at 90° C. for 3 days. After cooling to room temperature thered-brown mixture was poured into ice-water (3600 ml) and stirred for 1hour. The solution was neutralized with Na₂CO₃ (2 M solution in water)and extracted with dichloromethane (2.5 L). The organic phase was dried(Na₂SO₄) and the solvent was removed in vacuo. The remaining red-brownoil was purified by fractional distillation to afford the title compound(51 g, 39%).

¹H NMR (CDCl₃): δ 9.96 (s, 1H), 7.80 (d, 2H), 7.35 (d, 2H), 2.58 (m,1H), 1.94-1.70 (m, 5 H), 1.51-1.17 (m, 5H)

Other ligands of the invention include

-   -   3′,5′-Dichloro-4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-4-carboxylic        acid:

Example 260 General Procedure (C)5-(1-Bromo-6-hydroxynaphthalen-2-ylmethylene)-thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=350 (M+1); Rt.=3.45 min.

Example 261 General Procedure (C)5-[4-(2-Bromoethoxy)-naphthalen-1-ylmethylene]-thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=380 (M+1); Rt=3.52 min.

Example 262 General Procedure (C)5-(2-Methyl-5-nitro-1H-indol-3-ylmethylene)-thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=304 (M+1); Rt=2.95 min.

Example 263 General Procedure (C)5-(4-Naphthalen-2-yl-thiazol-2-ylmethylene)-thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=339 (M+1); Rt.=4.498 min.

Example 264 General Procedure (C)5-[4-(4-Methoxy-naphthalen-1-yl)-thiazol-2-ylmethylene]-thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=369 (M+1); Rt.=4.456 min.

Example 265 General Procedure (C)5-(2-Pyridin-4-yl-1H-indol-3-ylmethylene)-thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=322 (M+1); Rt.=2.307 min.

Example 266 General Procedure (C)5-[5-(4-Chlorophenyl)-1H-pyrazol-4-ylmethylene]-thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=306 (M+1); Rt.=3.60 min.

Example 267 General Procedure (C)5-[5-(2,5-Dimethylphenyl)-1H-pyrazol-4-ylmethylene]-thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=300 (M+1); Rt.=3.063 min.

Example 268 General Procedure (C)5-(2-Phenyl-benzo[d]imidazo[2,1-b]thiazol-3-ylmethylene)-thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=378 (M+1); Rt=3.90 min.

Example 269 General Procedure (C)N-{4-[2-(2,4-Dioxothiazolidin-5-ylidenemethyl)-phenoxy]-phenyl}-acetamide

HPLC-MS (Method C): m/z=355 (M+1); Rt 3.33 min.

Example 270 General Procedure (C)5-(2-Phenyl-imidazo[1,2-a]pyridin-3-ylmethylene)-thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=322 (M+1); Rt.=2.78 min.

Example 271 General Procedure (C)5-(2-Naphthalen-2-yl-imidazo[1,2-a]pyridin-3-ylmethylene)-thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=372 (M+1); Rt.=2.78 min.

Example 272 General Procedure (C)5-[6-Bromo-2-(3-methoxyphenyl)-imidazo[1,2-a]pyridin-3-ylmethylene]-thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=431 (M+1); Rt.=3.30 min.

Example 273 General Procedure (C)5-(1,2,3,4-Tetrahydrophenanthren-9-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=310 (M+1); Rt.=4.97 min.

Example 274 General Procedure (C)5-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=330 (M+1); Rt.=5.33 min.

Example 275 General Procedure (C)5-[6-(2,4-Dichloro-phenyl)-imidazo[2,1-b]thiazol-5-ylmethylene]-thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=396 (M+1); Rt.=3.82 min.

Example 276 General Procedure (C)5-(5-Bromobenzofuran-7-ylmethylene)-thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=324 (M+1); Rt.=3.82 min.

Example 277 General Procedure (C)4-[3-(2,4-Dioxothiazolidin-5-ylidenemethyl)-1,4-dimethylcarbazol-9-ylmethyl]-benzoicacid

HPLC-MS (Method C): m/z=457 (M+1); Rt=4.23 min.

Preparation of Intermediary Aldehyde:

1,4 Dimethylcarbazol-3-carbaldehyde (0.68 g, 3.08 mmol) was dissolved indry DMF (15 mL), NaH (diethyl ether washed) (0.162 g, 6.7 mol) wasslowly added under nitrogen and the mixture was stirred for 1 hour atroom temperature. 4-Bromomethylbenzoic acid (0.73 g, 3.4 mmol) wasslowly added and the resulting slurry was heated to 40° C. for 16 hours.Water (5 mL) and hydrochloric acid (6N, 3 mL) were added. After stirringfor 20 min at room temperature, the precipitate was filtered off andwashed twice with acetone to afford after drying 0.38 g (34%) of4-(3-formyl-1,4-dimethylcarbazol-9-ylmethyl)benzoic acid.

HPLC-MS (Method C): m/z=358 (M+1), RT.=4.15 min.

Example 278 General Procedure (C)4-[7-(2,4-Dioxothiazolidin-5-ylidenemethyl)-benzofuran-5-yl]-benzoicacid

Starting aldehyde commercially available (Syncom BV, NL)

HPLC-MS (Method C): m/z=366 (M+1); Rt.=3.37 min.

Example 279 General procedure (C)4-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)-2-nitrophenoxy]-benzoic acidmethyl ester

HPLC-MS (Method C): m/z=401 (M+1); Rt.=4.08 min.

Example 280 General Procedure (C)3′,5′-Dichloro-4′-(2,4-dioxothiazolidin-5-ylidenemethyl)-biphenyl-4-carboxylicacid

Starting aldehyde commercially available (Syncom BV, NL)

HPLC-MS (Method C): m/z=394 (M+1); Rt.=3.71 min.

Example 281 General Procedure (C)

HPLC-MS (Method C): m/z=232( M+1); Rt.=3.6 min.

Example 282 5-(2-Methyl-1H-indol-3-ylmethyl)-thiazolidine-2,4-dione

5-(2-Methyl-1H-indol-3-ylmethylene)thiazolidine-2,4-dione (prepared asdescribed in example 187,1.5 g, 5.8 mmol) was dissolved in pyridine (20mL) and THF (50 mL), LiBH₄ (2 M in THF, 23.2 mmol) was slowly added witha syringe under cooling on ice. The mixture was heated to 85° C. for 2days. After cooling, the mixture was acidified with concentratedhydrochloric acid to pH 1. The aquous layer was extracted 3 times withethyl acetate, dried with MgSO₄ treated with activated carbon, filteredand the resulting filtrate was evaporated in vacuo to give 1.3 g (88%)of the title compound.

HPLC-MS (Method C): m/z=261 (M+1); Rt.=3.00 min.

Example 2834-[4-(2,4-Dioxothiazolidin-5-ylmethyl)naphthalen-1-yloxy]butyric acid

4-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)naphthalen-1-yloxy]butyricacid (4.98 g, 13.9 mmol, prepared as described in example 469) wasdissolved in dry THF (50 mL) and added dry pyridine (50 mL) and, inportions, lithium borohydride (2.0 M, in THF, 14 mL). The resultingslurry was refluxed under nitrogen for 16 hours, added (after cooling)more lithium borohydride (2.0 M, in THF, 7 mL). The resulting mixturewas refluxed under nitrogen for 16 hours. The mixture was cooled andadded more lithium borohydride (2.0 M, in THF, 5 mL). The resultingmixture was refluxed under nitrogen for 16 hours. After cooling to 5°C., the mixture was added water (300 mL) and hydrochloric acid (150 mL).The solid was isolated by filtration, washed with water (3×500 mL) anddried. Recrystallization from acetonitrile (500 mL) afforded2.5 g of thetitle compound.

¹H-NMR (DMSO-d₆, selected peaks): δ=3.42 (1H, dd), 3.90 (1H, dd), 4.16(2H, “t”), 4.95 (1H, dd), 6.92 (1H, d), 7.31 (1H, d), 7.54 (1H, t), 7.62(1H, t), 8.02 (1H, d), 8.23 (1H, d), 12.1 (1H, bs), 12.2 (1H, bs).

HPLC-MS (Method C): m/z=382 (M+23); Rt=3.23 min.

Example 284 5-Naphthalen-1-ylmethylthiazolidine-2,4-dione

5-Naphthalen-1-ylmethylenethiazolidine-2,4-dione (1.08 g, 4.2 mmol,prepared as described in example 68) was dissolved in dry THF (15 mL)and added dry pyridine (15 mL) and, in portions, lithium borohydride(2.0 M, in THF, 4.6 mL). The resulting mixture was refluxed undernitrogen for 16 hours. After cooling to 5° C., the mixture was addedwater (100 mL), and, in portions, concentrated hydrochloric acid (40mL). More water (100 mL) was added, and the mixture was extracted withethyl acetate (200 mL). The organic phase was washed with water (3×100mL), dried and concentrated in vacuo. The residue was dissolved in ethylacetate (50 mL) added activated carbon, filtered and concentrated invacuo and dried to afford 0.82 g (75%) of the title compound.

¹H-NMR (DMSO-d₆): δ=3.54 (1H, dd), 3.98 (1H, dd), 5.00 (1H, dd), 7.4-7.6(4H, m), 7.87 (1H, d), 7.96 (1H, d), 8.11 (1H, d), 12.2 (1H, bs).HPLC-MS (Method C): m/z=258 (M+1); Rt=3.638 min.

The following preferred compounds of the invention may be preparedaccording to procedures similar to those described in the three examplesabove: Example 285

Example 286

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The following compounds are commercially available and may be preparedusing general procedures (B) and/or (C).

Example 380 5-(5-Bromo-1H-indol-3-ylmethylene)thiazolidine-2,4-dione

Example 381 5-Pyridin4-ylmethylenethiazolidine-2,4-dione

Example 382 5-(3-Bromo-4-methoxybenzylidene)thiazolidine-2,4-dione

Example 383 5-(3-Nitrobenzylidene)thiazolidine-2,4-dione

Example 384 5-Cyclohexylidene-1,3-thiazolidine-2,4-dione

Example 385 5-(3,4-Dihydroxybenzylidene)thiazolidine-2,4-dione

Example 386 5-(3-Ethoxy-4-hydroxybenzylidene)thiazolidine-2,4-dione

Example 3875-(4-Hydroxy-3-methoxy-5-nitrobenzylidene)thiazolidine-2,4-dione

Example 388 5-(3-Ethoxy-4-hydroxybenzylidene)thiazolidine-2,4-dione

Example 389 5-(4-Hydroxy-3,5-dimethoxybenzylidene)thiazolidine-2,4-dione

Example 3905-(3-Bromo-5-ethoxy-4-hydroxybenzylidene)thiazolidine-2,4-dione

Example 3915-(3-Ethoxy-4-hydroxy-5-nitrobenzylidene)thiazolidine-2,4-dione

Example 392

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Example 405 5-(3-Hydroxy-5-methyl-phenylamino)-thiazolidine-2,4-dione

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Example 4315-(4-Diethylamino-2-methoxy-benzylidene)-imidazolidine-2,4-dione

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Example 454 5-(4-Diethylamino-benzylidene)-2-imino-thiazolidin-4-one

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Example 459

General Procedure (D) for Preparation of Compounds of General Formula

wherein X, Y, and R³ are as defined above,

-   -   n is 1 or 3-20,    -   E is arylene or heterarylene (including up to four optional        substituents, R¹³, R¹⁴, R¹⁵, and R^(15A) as defined above),    -   R′ is a standard carboxylic acid protecting group, such as        C₁-C₆-alkyl or benzyl and Lea is a leaving group, such as        chloro, bromo, iodo, methanesulfonyloxy, toluenesulfonyloxy or        the like.

Step 1 is an alkylation of a phenol moiety. The reaction is preformed byreacting R¹⁰—C(═O)-E-OH with an ω-bromo-alkane-carboxylic acid ester (ora synthetic equivalent) in the presence of a base such as sodium orpotassium carbonate, sodium or potassium hydroxide, sodium hydride,sodium or potassium alkoxide in a solvent, such as DMF, NMP, DMSO,acetone, acetonitrile, ethyl acetate or isopropyl acetate. The reactionis performed at 20-160° C., usually at room temperature, but when thephenol moiety has one or more substituents heating to 50° C. or more canbe beneficial, especially when the substituents are in the orthoposition relatively to the phenol. This will readily be recognised bythose skilled in the art.

Step 2 is a hydrolysis of the product from step 1.

Step 3 is similar to general procedure (B) and (C).

This general procedure (D) is further illustrated in the followingexamples:

Example 460 General Procedure (D)4-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)phenoxy]butyric acid

Step 1:

A mixture of 4-hydroxybenzaldehyde (9.21 g, 75 mmol), potassiumcarbonate (56 g, 410 mmol) and 4-bromobutyric acid ethyl ester (12.9 mL,90 mmol) in N,N-dimethylformamide (250 mL) was stirred vigorously for 16hours at room temperature. The mixture was filtered and concentrated invacuo to afford 19.6 g (100%) of 4-(4-formylphenoxy)butyric acid ethylester as an oil. ¹H-NMR (DMSO-d₆): δ 1.21 (3H, t), 2.05 (2H, p), 2.49(2H, t), 4.12 (4H, m), 7.13 (2H, d), 7.87 (2H, d), 9.90 (1H, s). HPLC-MS(Method A): m/z=237 (M+1); R_(t)=3.46 min.

Step 2:

4-(4-Formylphenoxy)butyric acid ethyl ester (19.6 g, 75 mmol) wasdissolved in methanol (250 mL) and 1 N sodium hydroxide (100 mL) wasadded and the resulting mixture was stirred at room temperature for 16hours. The organic solvent was evaporated in vacuo (40° C., 120 mBar)and the residue was acidified with 1N hydrochloric acid (110 mL). Themixture was filtered and washed with water and dried in vacuo to afford14.3 g (91%) 4-(4-formylphenoxy)butyric acid as a solid. ¹H-NMR(DMSO-d₆): δ 1.99 (2H, p), 2.42 (2H, t), 4.13 (2H, t), 7.14 (2H, d),7.88 (2H, d), 9.90 (1H, s), 12.2 (1H, bs). HPLC-MS (Method A): m/z=209(M+1); R_(t)=2.19 min.

Step 3:

Thiazolidine-2,4-dione (3.55 g, 27.6 mmol), 4-(4-formylphenoxy)butyricacid (5.74 g, 27.6 mmol), anhydrous sodium acetate (11.3 g, 138 mmol)and acetic acid (100 mL) was refluxed for 16 h. After cooling, themixture was filtered and washed with acetic acid and water. Drying invacuo afforded 2.74 g (32%) of4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)phenoxy]butyric acid as asolid.

¹H-NMR (DMSO-d₆): δ 1.97 (2H, p), 2.40 (2H, t), 4.07 (2H, t), 7.08 (2H,d), 7.56 (2H, d), 7.77 (1H, s), 12.2 (1H, bs), 12.5 (1H, bs); HPLC-MS(Method A): m/z: 308 (M+1); Rt=2.89 min.

Example 461 General Procedure (D)[3-(2,4-Dioxothiazolidin-5-ylidenemethyl)phenoxy]acetic acid

Step 3:

Thiazolidine-2,4-dione (3.9 g, 33 mmol), 3-formylphenoxyacetic acid (6.0g, 33 mmol), anhydrous sodium acetate (13.6 g, 165 mmol) and acetic acid(100 mL) was refluxed for 16 h. After cooling, the mixture was filteredand washed with acetic acid and water. Drying in vacuo afforded 5.13 9(56%) of [3-(2,4-dioxothiazolidin-5-ylidenemethyl)phenoxy]acetic acid asa solid.

¹H-NMR (DMSO-d₆): δ 4.69 (2H, s), 6.95 (1H, dd), 7.09 (1H, t), 7.15 (1H,d), 7.39 (1H, t),7.53 (1H, s); HPLC-MS (Method A): m/z=280 (M+1) (poorionisation); R_(t)=2.49 min.

The compounds in the following examples were similarly prepared.

Example 462 General Procedure (D)3-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)phenyl]acrylic acid

¹H-NMR (DMSO-d₆): δ6.63 (1H, d), 7.59-7.64 (3H, m), 7.77 (1H, s), 7.83(2H, m).

Example 463 General Procedure (D)[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)phenoxy]acetic acid

Triethylamine salt: ¹H-NMR (DMSO-d₆): δ 4.27 (2H, s), 6.90 (2H, d), 7.26(1H, s), 7.40 (2H, d).

Example 464 General Procedure (D)4-(2,4-Dioxothiazolidin-5-ylidenemethyl)benzoic acid

Example 465 General Procedure (D)3-(2,4-Dioxothiazolidin-5-ylidenemethyl)benzoic acid

¹H-NMR (DMSO-d₆): δ 7.57 (1H, s), 7.60 (1H, t), 7.79 (1H, dt), 7.92 (1H,dt), 8.14 (1H, t).

Example 466 General Procedure (D)4-[2-Chloro-4-(2,4-dioxothiazolidin-5-ylidenemethyl)phenoxy]butyric acid

¹H-NMR (DMSO-d₆): δ 2.00 (2H, p), 2.45 (2H, t), 4.17 (2H, t), 7.31 (1H,d), 7.54 (1H, dd), 7.69 (1H, d), 7.74 (1H, s), 12.2 (1H, bs), 12.6 (1H,bs). HPLC-MS (Method A): m/z: 364 (M+23); Rt=3.19 min.

Example 467 General Procedure (D)4-[2-Bromo-4-(2,4-dioxothiazolidin-5-ylidenemethyl)phenoxy]butyric acid

¹H-NMR (DMSO-d₆): δ 1.99 (2H, p), 2.46 (2H, t), 4.17 (2H, t), 7.28 (1H,d), 7.57 (1H, dd), 7.25 (1H, s), 7.85 (1H, d), 12.2 (1H, bs), 12.6 (1H,bs). HPLC-MS (Method A): m/z: 410 (M+23); Rt=3.35 min.

Example 468 General Procedure (D)4-[2-Bromo-4-(4-oxo-2-thioxothiazolidin-5-ylidenemethyl)phenoxy]butyricacid

¹H-NMR (DMSO-d₆): δ 1.99 (2H, p), 2.45 (2H, t), 4.18 (2H, t), 7.28 (1H,d), 7.55 (1H, dd), 7.60 (1H, s), 7.86 (1H, d), 12.2 (1H, bs), 13.8 (1H,bs). HPLC-MS (Method A): m/z: 424 (M+23); Rt=3.84 min. HPLC-MS (MethodA): m/z: 424 (M+23); Rt=3,84 min

Example 469 General Procedure (D)4-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)naphthalen-1-yloxy]butyricacid

¹H-NMR (DMSO-d₆): δ 2.12 (2H, p), 2.5 (below DMSO), 4.28 (2H, t), 7.12(1H, d), 7.6-7.7 (3H, m), 8.12 (1H, d), 8.31 (1H, d), 8.39 (1H, s), 12.2(1H, bs), 12.6 (1H, bs). HPLC-MS (Method A): m/z: 380 (M+23); Rt=3.76min.

Example 470 General Procedure (D)5-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)naphthalen-1-yloxy]pentanoicacid

HPLC-MS (Method A): m/z: 394 (M+23); Rt=3.62 min. ¹H-NMR (DMSO-d₆): δ1.78 (2H, m), 1.90 (2H, m), 2.38 (2H, t), 4.27 (2H, t), 7.16 (1H, d),7.6-7.75 (3H, m), 8.13 (1H, d), 8.28 (1H, d), 8.39 (1H, s), 12.1 (1H,bs), 12.6 (1H, bs).

Example 4715-[2-Bromo-4-(2,4-dioxothiazolidin-5-ylidenemethyl)naphthalen-1-yloxy]pentanoicacid

5-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)-naphthalen-1-yloxy]pentanoicacid (example 470, 185 mg, 0.5 mmol) was treated with an equimolaramount of bromine in acetic acid (10 mL). Stirring at RT for 14 daysfollowed by evaporation to dryness afforded a mixture of the brominatedcompound and unchanged starting material. Purification by preparativeHPLC on a C18 column using acetonitrile and water as eluent afforded 8mg of the title compound.

HPLC-MS (Method C): m/z: 473 (M+23), Rt.=3.77 min

Example 4724-[2-Bromo-4-(2,4-dioxothiazolidin-5-ylidenemethyl)naphthalen-1-yloxy]butyricacid

Starting with4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)-naphthalen-1-yloxy]-butyricacid (example 469, 0.5 mmol) using the same method as in example 471afforded 66 mg of the title compound.

HPLC-MS (Method C): m/z: 459 (M+23); Rt.=3.59 min.

Example 473 General Procedure (D)[2-Bromo-4-(2,4-dioxothiazolidin-5-ylidenemethyl)phenoxy]acetic acid

¹H-NMR (DMSO-d₆): δ 4.90 (2H, s), 7.12 (1H, d), 7.52 (1H, dd), 7.65 (1H,s) 7.84 (1H, d).HPLC-MS (Method A): m/z: not observed; Rt=2.89 min.

Example 474 General Procedure (D)4-[3-(2,4-Dioxothiazolidin-5-ylidenemethyl)phenoxy]butyric acid

¹H-NMR (DMSO-d₆): δ 1.98 (2H, p), 2.42 (2H, t), 4.04 (2H, t), 7.05 (1H,dd), 7.15 (2H, m), 7.45 (1H, t), 7.77 (1H, s), 12.1 (1H, bs), 12.6 (1H,bs). HPLC-MS (Method A): m/z: 330 (M+23); Rt=3.05 min.

Example 475 General Procedure (D)[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)-3-methoxyphenoxy]acetic acid

HPLC-MS (Method B): m/z: 310 (M+1); Rt=3.43 min.

Example 476 General Procedure (D)[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)naphthalen-1-yloxy]acetic acid

HPLC-MS (Method A): m/z: 330 (M+1); Rt=3.25 min.

Example 477 General Procedure (D)8-(2,4-Dioxothiazolidin-5-ylidenemethyl)naphthalene-1-carboxylic acid

HPLC-MS (Method A): m/z: 299 (M+1); Rt=2.49 min.

Example 478 General Procedure (D)[3-(2,4-Dioxothiazolidin-5-ylidenemethyl)indol-1-yl]acetic acid

HPLC-MS (Method A): m/z: 303 (M+1); Rt=2.90 min.

Preparation of Starting Material:

3-Formylindol (10 g, 69 mmol) was dissolved in N,N-dimethylformamide(100 mL) and under an atmosphere of nitrogenand with external cooling,keeping the temperature below 15° C., sodium hydride (60% in mineraloil, 3.0 g, 76 mmol) was added in portions. Then a solution of ethylbromoacetate (8.4 mL, 76 mmol) in N,N-dimethylformamide (15 mL) wasadded dropwise over 30 minutes and the resulting mixture was stirred atroom temperature for 16 hours. The mixture was concentrated in vacuo andthe residue was partitioned between water (300 mL) and ethyl acetate(2×150 mL). The combined organic extracts were washed with a saturatedaqueous solution of ammonium chloride (100 mL), dried (MgSO₄) andconcentrated in vacuo to afford 15.9 g (quant.) of(3-formylindol-1-yl)acetic acid ethyl ester as an oil.

¹H-NMR (CDCl₃): δ_(H)=1.30 (3H, t), 4.23 (2H, q), 4.90 (2H, s), 7.3 (3H,m), 7.77 (1H, s), 8.32 (1H, d), 10.0 (1H, s).

(3-Formylindol-1-yl)acetic acid ethyl ester (15.9 g 69 mmol) wasdissolved in 1,4-dioxane (100 mL) and 1N sodium hydroxide (10 mL) wasadded and the resulting mixture was stirred at room temperature for 4days. Water (500 mL) was added and the mixture was washed with diethylether (150 mL). The aqueous phase was acidified with 5N hydrochloricacid and extracted with ethyl acetate (250+150 mL). The combined organicextracts were dried (MgSO₄) and concentrated in vacuo to afford 10.3 g(73%) of (3-formylindol-1-yl)acetic acid as a solid.

¹H-NMR (DMSO-d₆): δ_(H)=5.20 (2H, s), 7.3 (2H, m), 7.55 (1H, d), 8.12(1H, d), 8.30 (1H, s), 9.95 (1H, s), 13.3 (1H, bs).

Example 479 General Procedure (D)3-[3-(2,4-Dioxothiazolidin-5-ylidenemethyl)indol-1-yl]propionic acid

HPLC-MS (Method A): m/z: 317 (M+1); Rt=3.08 min.

Preparation of Starting Material:

A mixture of 3-formylindol (10 g, 69 mmol), ethyl 3-bromopropionate(10.5 mL, 83 mmol) and potassium carbonate (28.5 g, 207 mmol) andacetonitrile (100 mL) was stirred vigorously at refux temperature for 2days. After cooling, the mixture was filtered and the filtrate wasconcentrated in vacuo to afford 17.5 g (quant.) of3-(3-formylindol-1-yl)propionic acid ethyl ester as a solid.

¹H-NMR (DMSO-d₆): δ_(H)=1.10 (3H, t), 2.94 (2H, t), 4.02 (2H, q), 4.55(2H, t), 7.3 (2H, m), 7.67 (1H, d), 8.12 (1H, d), 8.30 (1H, s), 9.90(1H, s).

3-(3-Formylindol-1-yl)propionic acid ethyl ester (17.5 g 69 mmol) washydrolysed as described above to afford 12.5 g (83%) of3-(3-formylindol-1-yl)propionic acid as a solid.

¹H-NMR (DMSO-d₆): δ_(H)=2.87 (2H, t), 4.50 (2H, t), 7.3 (2H, m), 7.68(1H, d), 8.12 (1H, d), 8.31 (1H, s), 9.95 (1H, s), 12.5 (1H, bs).

Example 480 General Procedure (D){5-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)benzylidenel-4-oxo-2-thioxothiazolidin-3-yl}aceticacid

HPLC-MS (Method A): m/z: 429 (M+23); Rt=3.89 min.

Example 481 General Procedure (D)6-(2,4-Dioxothiazolidin-5-ylidenemethyl)naphthalen-2-yloxyoctanoic acid

HPLC-MS (Method C): m/z: 436 (M+23); Rt.=4.36 min

The intermediate aldehyde for this compound was prepared by a slightlymodified procedure: 6-Hydroxynaphthalene-2-carbaldehyde (1.0 g, 5.8mmol) was dissolved in DMF (10 mL) and sodium hydride 60% (278 mg) wasadded and the mixture stirred at RT for 15 min. 8-Bromooctanoic acid(0.37 g, 1.7 mmol) was converted to the sodium salt by addition ofsodium hydride 60% and added to an aliquot (2.5 mL) of the abovenaphtholate solution and the resulting mixture was stirred at RT for 16hours. Aqueous acetic acid (10%) was added and the mixture was extracted3 times with diethyl ether. The combined organic phases were dried withMgSO₄ and evaporated to dryness affording 300 mg of8-(6-formylnaphthalen-2-yloxy)octanoic acid.

HPLC-MS (Method C): m/z 315 (M+1); Rt.=4.24 min.

Example 482 General Procedure (D)12-[6-(2,4-Dioxothiazolidin-5-ylidenemethyl)naphthalen-2-yloxy]dodecanoicacid

HPLC-MS (Method C): m/z: 492 (M+23); Rt.=5.3 min.

The intermediate aldehyde was prepared similarly as described in example481.

Example 483 General Procedure (D)11-[6-(2,4-Dioxothiazolidin-5-ylidenemethyl)naphthalen-2-yloxy]undecanoicacid

HPLC-MS (Method C): m/z:478 (M+23); Rt.=5.17 min.

The intermediate aldehyde was prepared similarly as described in example481.

Example 484 General Procedure (D)15-[6-(2,4-Dioxothiazolidin-5-ylidenemethyl)naphthalen-2-yloxy]pentadecanoicacid

HPLC-MS (Method C): m/z: 534 (M+23); Rt.=6.07 min.

The intermediate aldehyde was prepared similarly as described in example481.

Example 485 General Procedure (D)6-[6-(2,4-Dioxothiazolidin-5-ylidenemethyl)naphthalen-2-yloxy]hexanoicacid

HPLC-MS (Method C): m/z: 408 (M+23); Rt.=3.71 min.

Example 486 General Procedure (D)4-[6-(2,4-Dioxothiazolidin-5-ylidenemethyl)naphthalen-2-yloxy]butyricacid

HPLC-MS (Method C): m/z: 380 (M+23); Rt.=3.23 min.

Example 487 General Procedure (D)6-[6-(2,4-Dioxothiazolidin-5-ylidenemethyl)naphthalen-2-yloxy]hexanoicacid ethyl ester

HPLC-MS (Method C): m/z: 436 (M+23); Rt.=4.64 min.

Example 488 General Procedure (D)4-[6-(2,4-Dioxothiazolidin-5-ylidenemethyl)naphthalen-2-yloxy]butyricacid ethyl ester

HPLC-MS (Method C): m/z: 408 (M+23); Rt.=4.28 min.

Example 489 General Procedure (D)2-{5-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)naphthalen-1-yloxy]pentyl}malonicacid

HPLC-MS (Method C): m/z=444 (M+1); Rt=3.84 min.

Example 490 General Procedure (D)2-{5-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)naphthalen-1-yloxy]pentyl}malonicacid diethyl ester

HPLC-MS (Method C): m/z=500 (M+1); Rt=5.18 min.

Example 491 General Procedure (D)4-[4-(2,4,6-Trioxotetrahydropyrimidin-5-ylidenemethyl)naphthalen-1-yloxy]butyricacid

HPLC-MS (Method C): m/z=369 (M+1); Rt=2.68 min.

Example 492N-(3-Aminopropyl)-4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)-naphthalen-1-yloxy]-butyramide

To a mixture of4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)naphthalen-1-yloxy]butyricacid (example 469, 5.9 g, 16.5 mmol) and 1-hydroxybenzotriazole (3.35 g,24.8 mmol) in DMF (60 mL) was added1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (4.75 g,24.8 mmol) and the resulting mixture was stirred at room temperature for2 hours. N-(3-amino-propylcarbamic acid tert-butyl ester (3.45 g, 19.8mmol) was added and the resulting mixture was stirred at roomtemperature for 16 hours. The mixture was concentrated in vacuo andethyl acetate and dichloromethane were added to the residue. The mixturewas filtered, washed with water and dried in vacuo to afford 4.98 g(59%) of(3-{4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)naphthalen-1-yloxy]butyrylamino}propyl)carbamicacid tert-butyl ester.

HPLC-MS (Method C): m/z: 515 (M+1); Rt=3.79 min.

(3-{4-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)naphthalen-1-yloxy]butyrylamino}-propyl)carbamicacid tert-butyl ester (4.9 g, 9.5 mmol) was added dichloromethane (50mL) and trifluoroacetic acid (50 mL) and the resulting mixture wasstirred at room temperature for 45 minutes. The mixture was concentratedin vacuo and co-evaporated with toluene. To the residue was added ethylacetate (100 mL) and the mixture was filtered and dried in vacuo toafford the title compound as the trifluoroacetic acid salt.

HPLC-MS (Method C): m/z: 414 (M+1); Rt=2.27 min.

Compounds of the Invention Includes: Example 493

Example 494

Example 495

Example 496

Example 497

Example 498

Example 499

Example 500

Example 501

Example 502

Example 503

Example 504 Prepared Analogously to General Procedure (D)2-{5-[4-(2,4-Thiazolidindion-5-ylidenemethyl)naphthalen-1-yloxy]pentyl}malonicacid

A solution of 4-hydroxy-1-naphtaldehyde (1.0 g, 5.81 mmol),2-(5-bromopentyl)malonic acid diethyl ester (2.07 g, 6.68 mmol) andpotassium carbonate (4.01 g, 29 mmol) in DMF (50 mL) was stirred at 100°C. for 3 hours. The mixture was cooled and the salt was filtered off.The solvent was then removed under reduced pressure to afford 2.9 g ofcrude 2-[5-(4-formylnaphtalen-1-yloxy)pentyl]malonic acid diethyl esterwhich was used for the next reaction without further purification.

HPLC-MS (Method C): m/z: 401 (M+1); Rt=5.16 min. ¹H-NMR (DMSO-d6):δ=1.18 (t, 6 H), 1.39 (m, 2 H), 1.55 (m, 2 H), 1.87 (m, 4 H), 3.48 (t, 1H), 4.13 (m, 4 H), 4.27 (t, 2 H), 7.17 (d, 1 H), 7.64(t, 1 H), 7.75 (t,1 H), 8.13 (d, 1 H), 8.29 (d, 1 H), 9.24 (d, 1 H), 10.19 (s, 1 H).

1.4 g (3.5 mmol) of crude 2-[5-(4-formylnaphtalen-1-yloxy)pentyl]malonicacid diethyl ester was treated with aqueous sodium hydroxide (1N, 8.75mL, 8.75 mmol) and methanol (50 mL). The solution was stirred at 70° C.for 5 hours and the mixture was concentrated under reduced pressure.Hydrochloric acid (6 N) was added until pH<2. The resulting slurry wasstirred untill it solidified. The crystals were filtered off, washedwith water and then dried in vacuo to afford 1.1 g (92%) of2-[5-(4-formylnaphtalen-1-yloxy)pentyl]malonic acid. The product wasused in the next step without further purification.

HPLC-MS (Method C): m/z: 345 (M+1); Rt=3.52 min. ¹H-NMR(DMSO-d6): δ=1.40(m, 2 H), 1.55 (m, 2 H), 1.80 (m, 2 H), 1.90 (m, 2 H), 3.24 (t, 1 H),4.29 (t, 2 H), 7.19 (d, 1 H), 7.64(t, 1 H), 7.75 (t, 1 H), 8.14 (d, 1H), 8.30 (d, 1 H), 9.23 (d, 1 H), 10.18 (s, 1 H), 12.69 (s, 2 H).

To a solution of 2-[5-(4-formylnaphtalen-1-yloxy) pentyl]malonic acid(0.36 g, 1.05 mmol) in acetic acid (10 mL) was added2,4-thiazolidindione (0.16 g,1.36 mmol) and piperidine (0.52 mL, 5.25mmol). The solution was heated to 105° C. for 24 hours. After cooling toroom temperature, the solvents were removed in vacuo. Water was added tothe residue. The precipitate was filtered off and washed with water.Recrystalisation from acetonitrile afforded 200 mg (43%) of the titlecompound as a solid.

HPLC-MS (Method C): m/z: 422 (M-CO₂+Na); Rt=4.08 min. ¹H-NMR(DMSO-d₆):δ=1.41 (m, 2 H), 1.55 (m, 4 H), 1.88 (m, 2 H), 2.23 (t, 1 H), 4.24 (t, 2H), 7.61-7.74 (m, 3 H), 8.12 (d, 1 H), 8.28 (d, 1 H), 8.38 (s, 1 H),12.00 (s, 1 H), 12.59 (s, 2 H).

The following compounds are commercially available and may be preparedaccording to general procedure (D):

Example 505

Example 506

Example 507

Example 508

Example 509

Example 510

Example 511

The following salicylic acid derivatives do all bind to the His B10 Zn²⁺ site of the insulin hexamer:

Example 512 Salicylic acid

Example 513 Thiosalicylic acid (or: 2-Mercaptobenzoic acid)

Example 514 2-Hydroxy-5-nitrobenzoic acid

Example 515 3-Nitrosalicyclic acid

Example 516 5,5′-Methylenedisalicylic acid

Example 517 2-Amino-5-trifluoromethylbenzoesyre

Example 518 2-Amino4-chlorobenzoic acid

Example 519 2-Amino-5-methoxybenzoesyre

Example 520

Example 521

Example 522

Example 523

Example 524

Example 525

Example 526 5-Iodosalicylic acid

Example 527 5-Chlorosalicylic acid

Example 528 1-Hydroxy-2-naphthoic acid

Example 529 3,5-Dihydroxy-2-naphthoic acid

Example 530 3-Hydroxy-2-naphthoic acid

Example 531 3,7-Dihydroxy-2-naphthoic acid

Example 532 2-Hydroxybenzo[a]carbazole-3-carboxylic acid

Example 533 7-Bromo-3-hydroxy-2-naphthoic acid

This compound was prepared according to Murphy et al., J. Med. Chem.1990, 33, 171-8.

HPLC-MS (Method A): m/z: 267 (M+1); Rt:=3.78 min.

Example 534 1,6-Dibromo-2-hydroxynaphthalene-3-carboxylic acid

This compound was prepared according to Murphy et al., J. Med. Chem.1990, 33, 171-8.

HPLC-MS (Method A): m/z: 346 (M+1); Rt:=4.19 min.

Example 535 7-Formyl-3-hydroxynaphthalene-2-carboxylic Acid

A solution of 7-bromo-3-hydroxynaphthalene-2-carboxylic acid (15.0 g,56.2 mmol) (example 533) in tetrahydrofuran (100 mL) was added to asolution of lithium hydride (893 mg, 112 20 mmol) in tetrahydrofuran(350 mL). After 30 minutes stirring at room temperature, the resultingsolution was heated to 50° C. for 2 minutes and then allowed to cool toambient temperature over a period of 30 minutes. The mixture was cooledto −78° C., and butyllithium (1.6 M in hexanes, 53 mL, 85 mmol) wasadded over a period of 15 minutes. N,N-Dimethylformamide (8.7 mL, 8.2 g,112 mmol) was added after 90 minutes additional stirring. The coolingwas discontinued, and the reaction mixture was stirred at roomtemperature for 17 hours before it was poured into 1 N hydrochloric acid(aq.) (750 mL). The organic solvents were evaporated in vacuo, and theresulting precipitate was filtered off and rinsed with water (3×100 mL)to yield the crude product (16.2 g). Purification on silica gel(dichloromethane/methanol/acetic acid=90:9:1) furnished the titlecompound as a solid.

¹H-NMR (DMSO-d6): δ 11.95 (1H, bs), 10.02 (1H, s), 8.61 (1H, s), 8.54(1H, s), 7.80 (2H, bs), 7.24 (1H, s); HPLC-MS (Method (A)): m/z: 217(M+1); Rt=2.49 min.

Example 536 3-Hydroxy-7-methoxy-2-naphthoic acid

Example 537 4-Amino-2-hydroxybenzoic acid

Example 538 5-Acetylamino-2-hydroxybenzoic acid

Example 539 2-Hydroxy-5-methoxybenzoic acid

The following compounds were prepared as described below:

Example 540 4-Bromo-3-hydroxynaphthalene-2-carboxylic acid

3-Hydroxynaphthalene-2-carboxylic acid (3.0 g, 15.9 mmol) was suspendedin acetic acid (40 mL) and with vigorous stirring a solution of bromine(817 μL, 15.9 mmol) in acetic acid (10 mL) was added drop wise during 30minutes. The suspension was stirred at room temperature for 1 hour,filtered and washed with water. Drying in vacuo afforded 3.74 g (88%) of4-bromo-3-hydroxynaphthalene-2-carboxylic acid as a solid.

¹H-NMR (DMSO-d₆): δ 7.49 (1H, t), 7.75 (1H, t), 8.07 (2H, “t”), 8.64(1H, s). The substitution pattern was confirmed by a COSY experiment,showing connectivities between the 3 (4 hydrogen) “triplets”. HPLC-MS(Method A): m/z: 267 (M+1); Rt=3.73 min.

Example 541 3-Hydroxy-4-iodonaphthalene-2-carboxylic acid

3-Hydroxynaphthalene-2-carboxylic acid (0.5 g, 2.7 mmol) was suspendedin acetic acid (5 mL) and with stirring iodine monochloride (135 μL, 2.7mmol) was added. The suspension was stirred at room temperature for 1hour, filtered and washed with water. Drying afforded 0.72 g (85%) of4-iodo-3-hydroxynaphthalene-2-carboxylic acid as a solid.

¹H-NMR (DMSO-d₆): δ 7.47 (1H, t), 7.73 (1H, t), 7.98 (1H, d), 8.05 (1H,d), 8.66 (1H, s). HPLC-MS (Method A): m/z: 315 (M+1); Rt=3.94 min.

Example 542 2-Hydroxy-5-[(4-methoxyphenylamino)methyl]benzoic acid

p-Anisidine (1.3 g, 10.6 mmol) was dissolved in methanol (20 mL) and5-formylsalicylic acid (1.75 g, 10.6 mmol)was added and the resultingmixture was stirred at room temperature for 16 hours. The solid formedwas isolated by filtration, re-dissolved in N-methyl pyrrolidone (20 mL)and methanol (2 mL). To the mixture was added sodium cyanoborohydride(1.2 g) and the mixture was heated to 70° C. for 3 hours. To the cooledmixture was added ethyl acetate (100 mL) and the mixture was extractedwith water (100 mL) and saturated aqueous ammonium chloride (100 mL).The combined aqueous phases were concentrated in vacuo and a 2 g aliquotwas purified by SepPac chromatography eluting with mixtures ofaetonitrile and water containing 0.1% trifluoroacetic acid to afford thetitle compound.

HPLC-MS (Method A): m/z: 274 (M+1); Rt=1.77 min. ¹H-NMR (methanol-d₄): δ3.82 (3H, s), 4.45 (2H, s), 6.96 (1H, d), 7.03 (2H, d), 7.23 (2H, d),7.45 (1 H, dd), 7.92 (1 H, d).

Example 543 2-Hydroxy-5-(4-methoxyphenylsulfamoyl)benzoic acid

A solution of 5-chlrosulfonylsalicylic acid (0.96 g, 4.1 mmol) indichloromethane (20 mL) and triethylamine (1.69 mL, 12.2 mmol) was addedp-anisidine (0.49 g, 4.1 mmol) and the resulting mixture was stirred atroom temperature for 16 hours. The mixture was added dichloromethane (50mL) and was washed with water (2×100 mL). Drying (MgSO₄) of the organicphase and concentration in vacuo afforded 0.57 g crude product.Purification by column chromatography on silica gel eluting first withethyl acetate:heptane (1:1) then with methanol afforded 0.1 g of thetitle compound.

HPLC-MS (Method A): m/z: 346 (M+23); Rt=2.89 min. ¹H-NMR (DMSO-d₆): δ3.67 (3H, s), 6.62 (1H, d), 6.77 (2H, d), 6.96 (2H, d), 7.40 (1H, dd),8.05 (1H, d), 9.6 (1H, bs).General Procedure (E) for Preparation of Compounds of General FormulaI₄:

wherein Lea is a leaving group such as Cl, Br, I or OSO₂CF₃, R ishydrogen or C₁-C₆-alkyl, optionally the two R-groups may together form a5-8 membered ring, a cyclic boronic acid ester, and J is as definedabove.

An analogous chemical transformation has previously been described inthe literature (Bumagin et al., Tetrahedron, 1997, 53, 14437-14450). Thereaction is generally known as the Suzuki coupling reaction and isgenerally performed by reacting an aryl halide or triflate with anarylboronic acid or a heteroarylboronic acid in the presence of apalladium catalyst and a base such as sodium acetate, sodium carbonateor sodium hydroxide. The solvent can be water, acetone, DMF, NMP, HMPA,methanol, ethanol toluene or a mixture of two or more of these solvents.The reaction is performed at room temperature or at elevatedtemperature. The general procedure (E) is further illustrated in thefollowing example:

Example 544 General Procedure (E)7-(4-Acetylphenyl)-3-hydroxynaphthalene-2-carboxylic Acid

To 7-bromo-3-hydroxynaphthalene-2-carboxylic acid (100 mg, 0.37 mmol)(example 533) was added a solution of 4-acetylphenylboronic acid (92 mg,0.56 mmol) in acetone (2.2 mL) followed by a solution of sodiumcarbonate (198 mg, 1.87 mmol) in water (3.3 mL). A suspension ofpalladium(II) acetate (4 mg, 0.02 mmol) in acetone (0.5 mL) was filteredand added to the above solution. The mixture was purged with N₂ andstirred vigorously for 24 hours at room temperature. The reactionmixture was poured into 1 N hydrochloric acid (aq.) (60 mL) and theprecipitate was filtered off and rinsed with water (3×40 mL). The crudeproduct was dissolved in acetone (25 mL) and dried with magnesiumsulfate (1 h). Filtration followed by concentration furnished the titlecompound as a solid (92 mg).

¹H-NMR (DMSO-d₆): δ 12.60 (1H, bs), 8.64 (1H, s), 8.42 (1H, s), 8.08(2H, d), 7.97 (2H, d), 7.92 (2H, m), 7.33 (1H, s), 2.63 (3H, s); HPLC-MS(Method (A): m/z: 307 (M+1); Rt=3.84 min.

The compounds in the following examples were prepared in a similarfashion. Optionally, the compounds can be further purified byrecrystallization from e.g. ethanol or by chromatography.

Example 545 General Procedure (E)3-Hydroxy-7-(3-methoxyphenyl)naphthalene-2-carboxylic acid

HPLC-MS (Method (A)): m/z: 295 (M+1); Rt=4.60 min.

Example 546 General Procedure (E)3-Hydroxy-7-phenylnaphthalene-2-carboxylic acid

HPLC-MS (Method (A)): m/z: 265 (M+1); Rt=4.6 min.

Example 547 General Procedure (E)3-Hydroxy-7-p-tolylnaphthalene-2-carboxylic acid

HPLC-MS (Method (A)): m/z: 279 (M+1); Rt=4.95 min.

Example 548 General Procedure (E)7-(4-Formylphenyl)-3-hydroxynaphthalene-2-carboxylic acid

HPLC-MS (Method (A)): m/z: 293 (M+1); Rt=4.4 min.

Example 549 General Procedure (E)6-Hydroxy-[1,2]binaphthalenyl-7-carboxylic acid

HPLC-MS (Method (A)): m/z: 315 (M+1); Rt=5.17 min.

Example 550 General Procedure (E)7-(4-Carboxy-phenyl)-3-hydroxynaphthalene-2-carboxylic acid

HPLC-MS (Method (A)): m/z: 309 (M+1); Rt=3.60 min.

Example 551 General Procedure (E)7-Benzofuran-2-yl-3-hydroxynaphthalene-2-carboxylic acid

HPLC-MS (Method (A)): m/z: 305 (M+1); Rt=4.97 min.

Example 552 General Procedure (E)3-Hydroxy-7-(4-methoxyphenyl)-naphthalene-2-carboxylic acid

HPLC-MS (Method (A)): m/z: 295 (M+1); Rt=4.68 min.

Example 553 General Procedure (E)7-(3-Ethoxyphenyl)-3-hydroxynaphthalene-2-carboxylic acid

HPLC-MS (Method (A)): m/z: 309 (M+1); Rt=4.89 min.

Example 554 General Procedure (E)7-Benzo[1,3]dioxol-5-yl-3-hydroxynaphthalene-2-carboxylic acid

HPLC-MS (Method (A)): m/z: 309 (M+1); Rt=5.61 min.

Example 555 General Procedure (E)7-Biphenyl-3-yl-3-hydroxynaphthalene-2-carboxylic acid

HPLC-MS (Method (A)): m/z: 341 (M+1); Rt=5.45 min.General Procedure (F) for Preparation of Compounds of General FormulaI₅:

wherein R³⁰ is hydrogen or C₁-C₆-alkyl and T is as defined above

This general procedure (F) is further illustrated in the followingexample:

Example 556 General Procedure (F)3-Hydroxy-7-[(4-(2-propyl)phenylamino)methyl]naphthalene-2-carboxylicAcid

7-Formyl-3-hydroxynaphthalene-2-carboxylic acid (40 mg, 0.19 mmol)(example 535) was suspended in methanol (300 μL). Acetic acid (16 μL, 17mg, 0.28 mmol) and 4-2-propyl)aniline (40 μL, 40 mg, 0.30 mmol) wereadded consecutively, and the resulting mixture was stirred vigorously atroom temperature for 2 hours. Sodium cyanoborohydride (1.0 M intetrahydrofuran, 300 μL, 0.3 mmol) was added, and the stirring wascontinued for another 17 hours. The reaction mixture was poured into 6 Nhydrochloric acid (aq.) (6 mL), and the precipitate was filtered off andrinsed with water (3×2 mL) to yield the title compound (40 mg) as itshydrochloride salt. No further purification was necessary.

¹H-NMR (DMSO-d₆): δ 10.95 (1H, bs), 8.45 (1H, s), 7.96 (1H, s), 7.78(1H, d), 7.62 (1H, d), 7.32 (1H, s), 7.13 (2H, bd), 6.98 (2H, bd), 4.48(2H, s), 2.79 (1H, sept), 1.14 (6H, d); HPLC-MS (Method (A)): m/z: 336(M+1); Rt=3.92 min.

The compounds in the following examples were made using this generalprocedure (F).

Example 557 General Procedure (F)7-{[(4-Bromophenyl)amino]methyl}-3-hydroxynaphthalene-2-carboxylic Acid

HPLC-MS (Method C): m/z: 372 (M+1); Rt=4.31 min.

Example 558 General Procedure (F)7-{[(3,5-Dichlorophenyl)amino]methyl}-3-hydroxynaphthalene-2-carboxylicAcid

HPLC-MS (Method C): m/z: 362 (M+1); Rt=4.75 min.

Example 559 General Procedure (F)7-{[(Benzothiazol-6-yl)amino]methyl}-3-hydroxynaphthalene-2-carboxylicAcid

HPLC-MS (Method C): m/z: 351 (M+1); Rt=3.43 min.

Example 560 General Procedure (F)3-Hydroxy-7-{[(quinolin-6-yl)amino]methyl}naphthalene-2-carboxylic Acid

HPLC-MS (Method C): m/z: 345 (M+1); Rt=2.26 min.

Example 561 General Procedure (F)3-Hydroxy-7-{[(4-methoxyphenyl)amino]methyl}naphthalene-2-carboxylicAcid

HPLC-MS (Method C): m/z: 324 (M+1); Rt=2.57 min.

Example 562 General Procedure (F)7-{[(2,3-Dihydrobenzofuran-5-ylmethyl)amino]methyl}-3-hydroxynaphthalene-2-carboxylicAcid

HPLC-MS (Method C): m/z: 350 (M+1); Rt=2.22 min.

Example 563 General Procedure (F)7-{[(4-Chlorobenzyl)amino]methyl}-3-hydroxynaphthalene-2-carboxylic Acid

HPLC-MS (Method C): m/z: 342 (M+1); Rt=2.45 min.

Example 564 General Procedure (F)3-Hydroxy-7-{[(naphthalen-1-ylmethyl)amino]methyl}naphthalene-2-carboxylicAcid

HPLC-MS (Method C): m/z: 357 (M+1); Rt=2.63 min.

Example 565 General Procedure (F)7-{[(Biphenyl-2-ylmethyl)amino]methyl}-3-hydroxynaphthalene-2-carboxylicAcid

HPLC-MS (Method C): m/z: 384 (M+1); Rt=2.90 min.

Example 566 General Procedure (F)3-Hydroxy-7-{[(4-phenoxybenzyl)amino]methyl}naphthalene-2-carboxylicAcid

HPLC-MS (Method C): m/z: 400 (M+1); Rt=3.15 min.

Example 567 General Procedure (F)3-Hydroxy-7-{[(4-methoxybenzyl)amino]methyl}naphthalene-2-carboxylicAcid

HPLC-MS (Method C): m/z: 338 (M+1); Rt=2.32 min.General Procedure (G) for Preparation of Compounds of General FormulaI₆:

wherein J is as defined above and the moiety (C₁-C₆-alkanoyl)₂O is ananhydride.

The general procedure (G) is illustrated by the following example:

Example 568 General Procedure (G)N-Acetyl-3-hydroxy-7-[(4-(2-propyl)phenylamino)methyl]naphthalene-2-carboxylicAcid

3-Hydroxy-7-[(4-(2-propyl)phenylamino)methyl]naphthalene-2-carboxylicacid (25 mg, 0.07 mmol) (example 556) was suspended in tetrahydrofuran(200 μL). A solution of sodium hydrogencarbonate (23 mg, 0.27 mmol) inwater (200 μL) was added followed by acetic anhydride (14 μL, 15 mg,0.15 mmol). The reaction mixture was stirred vigorously for 65 hours atroom temperature before 6 N hydrochloric acid (4 mL) was added. Theprecipitate was filtered off and rinsed with water (3×1 mL) to yield thetitle compound (21 mg). No further purification was necessary.

¹H-NMR (DMSO-d₆): δ 10.96 (1H, bs), 8.48 (1H, s), 7.73 (1H, s), 7.72(1H, d), 7.41 (1H, dd), 7.28 (1H, s), 7.23 (2H, d), 7.18 (2H, d), 4.96(2H, s), 2.85 (1H, sept), 1.86 (3H, s), 1.15 (6H, d); HPLC-MS (Method(A)): m/z: 378 (M+1); Rt=3.90 min.

The compounds in the following examples were prepared in a similarfashion.

Example 569 General Procedure (G)N-Acetyl-7-{[(4-bromophenyl)amino]methyl}-3-hydroxynaphthalene-2-carboxylicAcid

HPLC-MS (Method C): m/z: 414 (M+1); Rt=3.76 min.

Example 570 General Procedure (G)N-Acetyl-7-{[(2,3-dihydrobenzofuran-5-ylmethyl)amino]methyl}-3-hydroxynaphthalene-2-carboxylicAcid

HPLC-MS (Method C): m/z: 392 (M+1); Rt=3.26 min.

Example 571 General Procedure (G)N-Acetyl-7-{[(4-chlorobenzyl)amino]methyl}-3-hydroxynaphthalene-2-carboxylicAcid

HPLC-MS (Method C): m/z: 384 (M+1); Rt=3.67 min.

Compounds of the invention may also include tetrazoles:

Example 572 5-(3-(Naphthalen-2-yloxymethyl)-phenyl)-1H-tetrazole

To a mixture of 2-naphthol (10 g, 0.07 mol) and potassium carbonate (10g, 0.073 mol) in acetone (150 mL), alpha-bromo-m-tolunitril (13.6 g,0.07 mol) was added in portions. The reaction mixture was stirred atreflux temperature for 2.5 hours. The cooled reaction mixture wasfiltered and evaporated in vacuo affording an oily residue (19 g) whichwas dissolved in diethyl ether (150 mL) and stirred with a mixture ofactive carbon and MgSO₄ for 16 hours. The mixture was filtered andevaporated in vacuo affording crude 18.0 g (100%) of3-(naphthalen-2-yloxymethyl)-benzonitrile as a solid.

12 g of the above benzonitrile was recrystallised from ethanol (150 mL)affording 8.3 g (69%) of 3-(naphthalen-2-yloxymethyl)-benzonitrile as asolid.

M.p. 60-61° C. Calculated for C₁₈H₁₃NO: C, 83.37%; H, 5.05%; N, 5.40%;Found C, 83.51%; H, 5.03%; N, 5.38%.

To a mixture of sodium azide (1.46 g, 22.5 mmol) and ammonium chloride(1.28 g, 24.0 mmol) in dry dimethylformamide (20 mL) under an atmosphereof nitrogen, 3-(naphthalen-2-yloxymethyl)-benzonitrile (3.9 g, 15 mmol)was added and the reaction mixture was stirred at 125° C. for 4 hours.The cooled reaction mixture was poured on to ice water (300 mL) andacidified to pH=1 with 1 N hydrochloric acid. The precipitate wasfiltered off and washed with water, dried at 100° C. for 4 hoursaffording 4.2 g (93%) of the title compound.

M.p. 200-202° C. Calculated for C₁₈H₁₄N₄O: C, 71.51%; H, 4.67%; N,18.54%; Found C, 72.11%; H, 4.65%; N, 17.43%. ¹H NMR (400 MHz, DMSO-d₆)δ_(H) 5.36 (s, 2H), 7.29 (dd, 1H), 7.36 (dt, 1H), 7.47 (m, 2H), 7.66 (t,1H), 7.74 (d, 1H), 7.84 (m, 3H), 8.02 (d, 1H), 8.22 (s, 1H).

Example 573 N-(3-(Tetrazol-5-yl)phenyl)-2-naphtoic acid amide

2-Naphtoic acid (10 g, 58 mmol) was dissolved in dichloromethane (100mL) and N,N-dimethylformamide (0.2 mL) was added followed by thionylchloride (5.1 ml, 70 mmol). The mixture was heated at reflux temperaturefor 2 hours. After cooling to room temperature, the mixture was addeddropwise to a mixture of 3-aminobenzonitril (6.90 g, 58 mmol) andtriethyl amine (10 mL) in dichloromethane (75 mL). The resulting mixturewas stirred at room temperature for 30 minutes. Water (50 mL) was addedand the volatiles was exaporated in vacuo. The resulting mixture wasfiltered and the filter cake was washed with water followed by heptane(2×25 mL). Drying in vacuo at 50° C. for 16 hours afforded 15.0 g (95%)of N-(3-cyanophenyl)-2-naphtoic acid amide.

M.p. 138-140° C.

The above naphthoic acid amide (10 g, 37 mmol) was dissolved inN,N-dimethylformamide (200 mL) and sodium azide (2.63 g, 40 mmol) andammonium chloride (2.16 g, 40 mmol) were added and the mixture heated at125° C. for 6 hours. Sodium azide (1.2 g) and ammonium chloride (0.98 g)were added and the mixture heated at 125° C. for 16 hours. Aftercooling, the mixture was poured into water (1.5 l) and stirred at roomtemperature for 30 minutes. The solid formed was filtered off, washedwith water and dried in vacuo at 50° C. for 3 days affording 9.69 g(84%) of the title compound as a solid which could be further purifiedby treatment with ethanol at reflux temperature.

¹H NMR (200 MHz, DMSO-d₆): δ_(H) 7.58-7.70 (m, 3H), 7.77 (d, 1H),8.04-8.13 (m, 5H), 8.65 d, 1H), 10.7 (s, 1H).

Calculated for C₁₈H₁₃N₅O, 0.75 H₂O: C, 65.74%; H, 4.44%; N, 21.30%.Found: C, 65.58%; H, 4.50%; N, 21.05%.

Example 574 5-[3-(Biphenyl4-yloxymethyl)phenyl]-1H-tetrazole

To a solution of 4-phenylphenol (10.0 g, 59 mmol) in dryN,N-dimethyl-formamide (45 mL) kept under an atmosphere of nitrogen,sodium hydride (2.82 g, 71 mmol, 60% dispersion in oil) was added inportions and the reaction mixture was stirred until gas evolutionceased. A solution of m-cyanobenzyl bromide (13 g, 65 mmol) in dryN,N-dimethylformamide (45 mL) was added dropwise and the reactionmixture was stirred at room temperature for 18 hours. The reactionmixture was poured on to ice water (150 mL). The precipitate wasfiltered of and washed with 50% ethanol

(3×50 mL), ethanol (2×50 mL), diethyl ether (80 mL), and dried in vacuoat 50° C. for 18 hours affording crude 17.39 g of3-(biphenyl-4-yloxymethyl)-benzonitrile as a solid.

¹H NMR (200 MHz, CDCl₃) δ_(H) 5.14 (s, 2H), 7.05 (m, 2H), 7.30-7.78 (m,11H).

To a mixture of sodium azide (2.96 g, 45.6 mmol) and ammonium chloride(2.44 g, 45.6 mmol) in dry N,N-dimethylformamide (100 mL) under anatmosphere of nitrogen, 3-(biphenyl-4-yloxymethyl)-benzonitrile (10.0 g,35.0 mmol) was added and the reaction mixture was stirred at 125° C. for18 hours. The cooled reaction mixture was poured on to a mixture of 1Nhydrochloric acid (60 mL) and ice water (500 mL). The precipitate wasfiltered off and washed with water (3×100 mL), 50% ethanol (3×100 mL),ethanol (50 mL), diethyl ether (50 mL), ethanol (80 mL), and dried invacuo at 50° C. for 18 hours affording 8.02 g (70%) of the titlecompound.

¹H NMR (200 MHz, DMSO-d₆) δ_(H) 5.31 (s, 2H), 7.19 (m, 2H), 7.34 (m,1H), 7.47 (m, 2H), 7.69 (m, 6H), 8.05 (dt, 1H), 8.24 (s, 1H).

Example 575 5-(3-Phenoxymethyl)-phenyl)-tetrazole

3-Bromomethylbenzonitrile (5.00 g, 25.5 mmol) was dissolved inN,N-dimethylformamide (50 mL), phenol (2.40 g, 25.5 mmol) and potassiumcarbonate (10.6 g, 77 mmol) were added. The mixture was stirred at roomtemperature for 16 hours. The mixture was poured into water (400 mL) andextracted with ethyl acetate (2×200 mL). The combined organic extractswere washed with water (2×100 mL), dried (MgSO₄) and evaporated in vacuoto afford 5.19 g (97%) 3-(phenoxymethyl)benzonitrile as an oil.

TLC: R_(f)=0.38 (Ethyl acetate/heptane=1:4)

The above benzonitrile (5.19 g, 24.8 mmol) was dissolved inN,N-dimethylformamide (100 mL) and sodium azide (1.93 g, 30 mmol) andammonium chloride (1.59 g, 30 mmol) were added and the mixture washeated at 140° C. for 16 hours. After cooling, the mixture was pouredinto water (800 mL). The aqeous mixture was washed with ethyl acetate(200 mL). The pH of the aqueous phase was adjusted to 1 with 5 Nhydrochloric acid and stirred at room temperature for 30 minutes.Filtration, washing with water and drying in vacuo at 50° C. afforded2.06 g (33%) of the title compound as a solid.

¹H NMR (200 MHz, CDCl₃+DMSO-d₆) δ_(H) 5.05 (s, 2H), 6.88 (m, 3H), 7.21(m, 2H), 7.51 (m, 2H), 7.96 (dt, 1H), 8.14 (s, 1H).

Example 576 5-[3-(Biphenyl-4-ylmethoxy)phenyl]-1H-tetrazole

To a solution of 3-cyanophenol (5.0 g, 40.72 mmol) in dryN,N-dimethylformamide (100 mL) kept under an atmosphere of nitrogen,sodium hydride (2 g, 48.86 mmol, 60% dispersion in oil) was added inportions and the reaction mixture was stirred until gas evolutionceased. p-Phenylbenzyl chloride (9.26 g, 44.79 mmol) and potassiumiodide (0.2 g, 1.21 mmol) were added and the reaction mixture wasstirred at room temperature for 60 hours. The reaction mixture waspoured on to a mixture of saturated sodium carbonate (100 mL) and icewater (300 mL). The precipitate was filtered of and washed with water(3×100 mL), n-hexane (2×80 mL) and dried in vacuo at 50° C. for 18 hoursaffording 11.34 g (98%) of 3-(biphenyl-4-ylmethoxy)-benzonitrile as asolid.

To a mixture of sodium azide (2.37 g, 36.45 mmol) and ammonium chloride(1.95 g, 36.45 mmol) in dry N,N-dimethylformamide (100 mL) under anatmosphere of nitrogen, 3-(biphenyl-4-ylmethoxy)-benzonitrile (8.0 g,28.04 mmol) was added and the reaction mixture was stirred at

125° C. for 18 hours. To the cooled reaction mixture water (100 mL) wasadded and the reaction mixture stirred for 0.75 hour. The precipitatewas filtered off and washed with water, 96% ethanol (2×50 mL), and driedin vacuo at 50° C. for 18 hours affording 5.13 g (56%) of the titlecompound.

¹H NMR (200 MHz, DMSO-d₆) δ_(H) 5.29 (s, 2H), 7.31 (dd, 1H), 7.37-7.77(m, 12H).

Example 577 5-[4-(Biphenyl-4-ylmethoxy)-3-methoxyphenyl]-1H-tetrazol

This compound was made similarly as described in example 576.

Example 578

Example 579 5-(2-Naphtylmethyl)-1H-tetrazole

This compound was prepared similarly as described in example 572, step2.

Example 580 5-(1-Naphtylmethyl)-1H-tetrazole

This compound was prepared similarly as described in example 572, step2.

Example 581 5-[4-(Biphenyl-4-yloxymethyl)phenyl]-1H-tetrazole

A solution of alpha-bromo-p-tolunitrile (5.00 g, 25.5 mmol),4-phenylphenol (4.56 g, 26.8 mmol), and potassium carbonate (10.6 g,76.5 mmol) in N,N-dimethylformamide (75 mL) was stirred vigorously for16 hours at room temperature. Water (75 mL) was added and the mixturewas stirred at room temperature for 1 hour. The precipitate was filteredoff and washed with thoroughly with water. Drying in vacuo over night at50° C. afforded 7.09 g (97%) of 4-(biphenyl-4-yloxymethyl)benzonitrileas a solid.

The above benzonitrile (3.00 g, 10.5 mmol) was dissolved inN,N-dimethylformamide (50 mL), and sodium azide (1.03 g, 15.8 mmol) andammonium chloride (0.84 g, 15.8 mmol) were added and the mixture wasstirred 16 hours at 125° C. The mixture was cooled to room temperatureand water (50 mL) was added. The suspension was stirred overnight,filtered, washed with water and dried in vacuo at 50° C. for 3 days togive crude 3.07 g (89%) of the title compound. From the mother liquorcrystals were colected and washed with water, dried by suction to give0.18 g

(5%) of the title compound as a solid.

¹H NMR (200 MHz, DMSO-d₆): δ_(H) 5.21 (s, 2H), 7.12 (d, 2H), 7.30 (t,1H), 7.42 (t, 2H), 7.56-7.63 (m, 6H), 8.03 (d, 2H).

Calculated for C₂₀H₁₆N₄O, 2H₂O: C, 65.92%; H, 5.53%; N, 15.37%. Found:C, 65.65%; H, 5.01%; N, 14.92%.

Example 582

This compound was prepared similarly as described in example 576.

Example 583

Example 584

Example 585

Example 586 5-(3-(Biphenyl-4-yloxymethyl)-benzyl)-1H-tetrazole

Example 587 5-(1-Naphthyl)-1H-tetrazole

This compound was prepared similarly as described in example 572, step2.

Example 5885-[3-Methoxy-4-(4-methylsulfonylbenzyloxy)phenyl]-1H-tetrazole

This compound was made similarly as described in example 576.

Example 589 5-(2-Naphthyl)-1H-tetrazole

This compound was prepared similarly as described in example 572, step2.

Example 590 2-Amino-N-(1H-tetrazol-5-yl)-benzamide

Example 591 5-(4-Hydroxy-3-methoxyphenyl)-1H-tetrazole

This compound was prepared similarly as described in example 572, step2.

Example 592 4-(2H-Tetrazol-5-ylmethoxy)benzoic acid

To a mixture of methyl 4-hydroxybenzoate (30.0 9, 0.20 mol), sodiumiodide (30.0 g, 0.20 mol) and potassium carbonate (27.6 g, 0.20 mol) inacetone (2000 mL) was added chloroacetonitrile (14.9 g, 0.20 mol). Themixture was stirred at RT for 3 days. Water was added and the mixturewas acidified with 1N hydrochloric acid and the mixture was extractedwith diethyl ether. The combined organic layers were dried over Na₂SO₄and concentrated in vacuo. The residue was dissolved in acetone andchloroacetonitrile (6.04 g,0.08 mol), sodium iodide (12.0 g, 0.08 mol)and potassium carbonate (11.1 g, 0.08 mol) were added and the mixturewas stirred for 16 hours at RT and at 60° C. More chloroacetonitrile wasadded until the conversion was 97%. Water was added and the mixture wasacidified with 1N hydrochloric acid and the mixture was extracted withdiethyl ether. The combined organic layers were dried over Na₂SO₄ andconcentrated in vacuo to afford methyl 4-cyanomethyloxybenzoate inquantitative yield. This compound was used without further purificationin the following step.

A mixture of methyl 4-cyanomethyloxybenzoate (53.5 g,0.20 mol), sodiumazide (16.9 g, 0.26 mol) and ammonium chloride (13.9 g, 0.26 mol) in DMF1000 (mL) was refluxed overnight under N₂. After cooling, the mixturewas concentrated in vacuo. The residue was suspended in cold water andextracted with ethyl acetate. The combined organic phases were washedwith brine, dried over Na₂SO₄ and concentrated in vacuo, to affordmethyl 4-(2H-tetrazol-5-ylmethoxy)benzoate. This compound was used assuch in the following step.

Methyl 4-(2H-Tetrazol-5-ylmethoxy)-benzoate was refluxed in 3N sodiumhydroxide. The reaction was followed by TLC (DCM:MeOH=9:1). The reactionmixture was cooled, acidified and the product filtered off. The impureproduct was washed with DCM, dissolved in MeOH, filtered and purified bycolumn chromatography on silica gel (DCM:MeOH=9:1).The resulting productwas recrystallised from DCM:MeOH=95:5. This was repeated until theproduct was pure. This afforded 13.82 g (30%) of the title compound.

¹H-NMR (DMSO-d₆): 4.70 (2H, s), 7.48 (2H, d), 7.73 (2H, d), 13 (1H, bs).

Example 593 4-(2H-Tetrazol-5-ylmethylsulfanyl)benzoic acid

To a solution of sodium hydroxide (10.4 g, 0.26 mol) in degassed water(600 mL) was added 4-mercaptobenzoic acid (20.0 g, 0.13 mol). Thissolution was stirred for 30 minutes. To a solution of potassiumcarbonate (9.0 g, 65 mmol) in degassed water (400 mL) was addedchloroacetonitrile (9.8 g, (0.13 mol) portion-wise. These two solutionswere mixed and stirred for 48 hours at RT under N₂. The mixture wasfiltered and washed with heptane. The aqueous phase was acidified with3N hydrochloric acid and the product was filtered off, washed with waterand dried, affording 4-cyanomethylsulfanylbenzoic acid (27.2 g, 88%).This compound was used without further purification in the followingstep.

A mixture of 4-cyanomethylsulfanylbenzoic acid (27.2 g, 0.14 mol),sodium azide (11.8 g, 0,18 mol) and ammonium chloride (9.7 g, 0.18 mol)in DMF (1000 mL) was refluxed overnight under N₂. The mixture wasconcentrated in vacuo. The residue was suspended in cold water andextracted with diethyl ether. The combined organic phases were washedwith brine, dried over Na₂SO₄ and concentrated in vacuo. Water was addedand the precipitate was filtered off. The aqueous layer was concentratedin vacuo, water was added and the precipitate filtered off. The combinedimpure products were purified by column chromatography usingDCM:MeOH=9:1 as eluent, affording the title compound (5.2 g, 16%).

¹H-NMR (DMSO-d₆): 5.58 (2H, s), 7.15 (2H, d), 7.93 (2H, d), 12.7 (1H,bs).

Example 594 3-(2H-Tetrazol-5-yl)-9H-carbazole

3-Bromo-9H-carbazole was prepared as described by Smith et al. inTetrahedron 1992, 48, 7479-7488.

A solution of 3-bromo-9H-carbazole (23.08 g, 0.094 mol) and cuprouscyanide (9.33 g, 0.103 mol) in N-methyl-pyrrolidone (300 ml) was heatedat 200° C. for 5 h. The cooled reaction mixture was poured on to water(600 ml) and the precipitate was filtered off and washed with ethylacetate (3×50 ml). The filtrate was extracted with ethyl acetate (3×250ml) and the combined ethyl acetate extracts were washed with water (150ml), brine (150 ml), dried (MgSO₄) and concentrated in vacuo. Theresidue was crystallised from heptanes and recrystallised fromacetonitrile (70 ml) affording 7.16 g (40%) of 3-cyano-9H-carbazole as asolid. M.p. 180-181° C.

3-Cyano-9H-carbazole (5.77 g, 30 mmol) was dissolved inN,N-dimethylformamide (150 ml), and sodium azide (9.85 g, 152 mmol),ammonium chloride (8.04 g, 150 mmol) and lithium chloride (1.93 g, 46mmol) were added and the mixture was stirred for 20 h at 125° C. To thereaction mixture was added an additional portion of sodium azide (9.85g, 152 mmol) and ammonium chloride (8.04 g, 150 mmol) and the reactionmixture was stirred for an additional 24 h at 125° C. The cooledreaction mixture was poured on to water (500 ml). The suspension wasstirred for 0.5 h, and the precipitate was filtered off and washed withwater (3×200 ml) and dried in vacuo at 50° C. The dried crude productwas suspended in diethyl ether (500 ml) and stirred for 2 h, filteredoff and washed with diethyl ether (2×200 ml) and dried in vacuo at 50°C. affording 5.79 g (82%) of the title compound as a solid.

¹H-NMR (DMSO-d₆): δ 11.78 (1H, bs), 8.93 (1H, d), 8.23 (1H, d), 8.14(1H, dd), 7.72 (1H, d), 7.60 (1H, d), 7.49 (1H, t), 7.28 (1H, t);HPLC-MS (Method C): m/z: 236 (M+1); Rt=2.77 min.

The following commercially available tetrazoles do all bind to the HisB10 Zn²⁺ site of the insulin hexamer:

Example 595 5-(3-Tolyl)-1H-tetrazole

Example 596 5-(2-Bromophenyl)tetrazole

Example 597 5-(4-Ethoxalylamino-3-nitrophenyl)tetrazole

Example 598

Example 599

Example 600

Example 601

Example 602 Tetrazole

Example 603 5-Methyltetrazole

Example 604 5-Benzyl-2H-tetrazole

Example 605 4-(2H-Tetrazol-5-yl)benzoic acid

Example 606 5-Phenyl-2H-tetrazole

Example 607 5-(4-Chlorophenylsulfanylmethyl)-2H-tetrazole

Example 608 5-(3-Benzyloxyphenyl)-2H-tetrazole

Example 609 2-Phenyl-6-(1H-tetrazol-5-yl)-chromen-4-one

Example 610

Example 611

Example 612

Example 613

Example 614

Example 615 5-(4-Bromo-phenyl)-1H-tetrazole

Example 616

Example 617

Example 618

Example 619

Example 620

Example 621

Example 622

Example 623

Example 624

Example 625

Example 626

Example 627

Example 628

Example 629

Example 630

Example 631

Example 632

Example 633

Example 634

Example 635

Example 636

Example 637

Example 638

Example 639

Example 640

Example 641

Example 642

Example 643

Example 644

Example 645

Example 646 5-(2,6-Dichlorobenzyl)-2H-tetrazole

General Procedure (H) for Preparation of Compounds of General FormulaI₇:

wherein K, M, and T are as defined above.

The reaction is generally known as a reductive alkylation reaction andis generally performed by stirring an aldehyde with an amine at low pH(by addition of an acid, such as acetic acid or formic acid) in asolvent such as THF, DMF, NMP, methanol, ethanol, DMSO, dichloromethane,1,2-dichloroethane, trimethyl orthoformate, triethyl orthoformate, or amixture of two or more of these. As reducing agent sodium cyanoborohydride or sodium triacetoxy borohydride may be used. The reactionis performed between 20° C. and 120° C., preferably at room temperature.

When the reductive alkylation is complete, the product is isolated byextraction, filtration, chromatography or other methods known to thoseskilled in the art.

The general procedure (H) is further illustrated in the followingexample 647:

Example 647 General Procedure (H)Biphenyl-4-ylmethyl-[3-(2H-tetrazol-5-yl)phenyl]amine

A solution of 5-(3-aminophenyl)-2H-tetrazole (example 874, 48 mg, 0.3mmol) in DMF (250 μL) was mixed with a solution of4-biphenylylcarbaldehyde (54 mg, 0.3 mmol) in DMF (250 μL) and aceticacid glacial (250 μL) was added to the mixture followed by a solution ofsodium cyano borohydride (15 mg, 0.24 mmol) in methanol (250 μL). Theresulting mixture was shaken at room temperature for 2 hours. Water (2mL) was added to the mixture and the resulting mixture was shaken atroom temperature for 16 hours. The mixture was centrifugated (6000 rpm,10 minutes) and the supernatant was removed by a pipette. The residuewas washed with water (3 mL), centrifugated (6000 rpm, 10 minutes) andthe supernatant was removed by a pipette. The residue was dried in vacuoat 40° C. for 16 hours to afford the title compound as a solid.

HPLC-MS (Method C): m/z: 328 (M+1), 350 (M+23); Rt=4.09 min.

Example 648 General Procedure (H)Benzyl-[3-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 252 (M+1); Rt=3.74 min.

Example 649 General Procedure (H)(4-Methoxybenzyl)-[3-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 282.2 (M+1); Rt=3.57 min.

Example 650 General Procedure (H)4-{[3-(2H-Tetrazol-5-yl)phenylamino]methyl}phenol

HPLC-MS (Method D): m/z: 268,4 (M+1); Rt=2.64 min.

Example 651 General Procedure (H)(4-Nitrobenzyl)-[3-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 297.4 (M+1); Rt=3.94 min.

Example 652 General Procedure (H)(4-Chlorobenzyl)-[3-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 287.2 (M+1); Rt=4.30 min.

Example 653 General Procedure (H)(2-Chlorobenzyl)-[3-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 286 (M+1); Rt=4.40 min.

Example 654 General Procedure (H)(4-Bromobenzyl)-[3-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z:332 (M+1); Rt=4.50 min.

Example 655 General Procedure (H)(3-Benzyloxybenzyl)-[3-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 358 (M+1); Rt=4.94 min.

Example 656 General Procedure (H)Naphthalen-1-ylmethyl-[3-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 302 (M+1); Rt=4.70 min.

Example 657 General Procedure (H)Naphthalen-2-ylmethyl-[3-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 302 (M+1); Rt=4.60 min.

Example 658 General Procedure (H)4-{[3-(2H-Tetrazol-5-yl)phenylamino]methyl}benzoic acid

HPLC-MS (Method D): m/z: 296 (M+1); Rt=3.24 min.

Example 659 General Procedure (H)[3-(2H-Tetrazol-5-yl)-phenyl]-[3-(3-trifluoromethyl-phenoxy)benzyl]amine

HPLC-MS (Method D): m/z: 412 (M+1); Rt=5.54 min.

Example 660 General Procedure (H)(3-Phenoxybenzyl)-[3-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 344 (M+1); Rt=5.04 min.

Example 661 General Procedure (H)(4-Phenoxy-benzyl)-[3-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 344 (M+1); Rt=5.00 min.

Example 662 General Procedure (H)(4-{[3-(2H-Tetrazol-5-yl)phenylamino]methyl}phenoxy)acetic acid

HPLC-MS (Method D): m/z: 326 (M+1); Rt=3.10 min.

Example 663 General Procedure (H)(4-Benzyloxybenzyl)-[3-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 358 (M+1); Rt=4.97 min.

Example 664 General Procedure (H)3-(4-{[3-(2H-Tetrazol-5-yl)phenylamino]methyl}phenyl)acrylic acid

HPLC-MS (Method D): m/z: 322 (M+1); Rt=3.60 min.

Example 665 General Procedure (H)Dimethyl-(4-{[3-(2H-tetrazol-5-yl)phenylamino]methyl}naphthalen-1-yl)amine

HPLC-MS (Method D): m/z: 345 (M+1); Rt=3.07 min.

Example 666 General Procedure (H)(4′-Methoxybiphenyl-4-ylmethyl)-[3-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 358 (M+1); Rt=4.97 min.

Example 667 General Procedure (H)(2′-Chlorobiphenyl-4-ylmethyl)-[3-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 362 (M+1); Rt=5.27 min.

Example 668 General Procedure (H)Benzyl-[4-(2H-tetrazol-5-yl)phenyl]amine

For preparation of starting material, see example 875.

HPLC-MS (Method D): m/z: 252 (M+1); Rt=3.97 min.

Example 669 General Procedure (H)(4-Methoxybenzyl)-[4-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 282 (M+1); Rt=3.94 min.

Example 670 General Procedure (H)4-{[4-(2H-Tetrazol-5-yl)phenylamino]methyl}phenol

HPLC-MS (Method D): m/z: 268 (M+1); Rt=3.14 min.

Example 671 General Procedure (H)(4-Nitrobenzyl)-[4-2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: (M+1); Rt=3.94 min.

Example 672 General Procedure (H)(4-Chlorobenzyl)-[4-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: (M+1); Rt=4.47 min.

Example 673 General Procedure (H)(2-Chlorobenzyl)-[4-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 286 (M+1); Rt=4.37 min.

Example 674 General Procedure (H)(4-Bromobenzyl)-[4-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 331 (M+1); Rt=4.57 min.

Example 675 General Procedure (H)(3-Benzyloxybenzyl)-[4-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 358 (M+1); Rt=5.07 min.

Example 676 General Procedure (H)Naphthalen-1-ylmethyl-[4-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 302 (M+1); Rt=4.70 min.

Example 677 General Procedure (H)Naphthalen-2-ylmethyl-[4-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 302 (M+1); Rt=4.70 min.

Example 678 General Procedure (H)Biphenyl-4-ylmethyl-[4-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 328 (M+1); Rt=5.07 min.

Example 679 General Procedure (H)4-{[4-(2H-Tetrazol-5-yl)phenylamino]methyl}benzoic acid

HPLC-MS (Method D): m/z: 296 (M+1); Rt=3.34 min.

Example 680 General Procedure (H)[4-(2H-Tetrazol-5-yl)phenyl]-[3-(3-trifluoromethylphenoxy)benzyl]amine

HPLC-MS (Method D): m/z: 412 (M+1); Rt=5.54 min.

Example 681 General Procedure (H)(3-Phenoxybenzyl)-[4-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 344 (M+1); Rt=5.07 min.

Example 682 General Procedure (H)(4-Phenoxybenzyl)-[4-(2H-tetrazol-5-yl)-phenyl]-amine

HPLC-MS (Method D): m/z: 344 (M+1); Rt=5.03 min.

Example 683 General Procedure (H)3-{[4-(2H-Tetrazol-5-yl)phenylamino]methyl}benzoic acid

HPLC-MS (Method D): m/z: 286 (M+1); Rt=3.47 min.

Example 684 General Procedure (H)(4-{[4-(2H-Tetrazol-5-yl)phenylamino]methyl}phenoxy)acetic acid

HPLC-MS (Method D): m/z: 326 (M+1); Rt=3.40 min.

Example 685 General Procedure (H)(4-Benzyloxybenzyl)-[4-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 358 (M+1); Rt=5.14 min.

Example 686 General Procedure (H)3-(4-{[4-(2H-Tetrazol-5-yl)phenylamino]methyl}phenyl)acrylic acid

HPLC-MS (Method D): m/z: 322 (M+1); Rt=3.66 min.

Example 687 General Procedure (H)Dimethyl-(4-{[4-(2H-tetrazol-5-yl)phenylamino]methyl}naphthalen-1-yl)amine

HPLC-MS (Method D): m/z: 345 (M+1); Rt=3.10 min.

Example 688 General Procedure (H)(4′-Methoxybiphenyl-4-ylmethyl)-[4-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 358 (M+1); Rt=5.04 min.

Example 689 General Procedure (H)(2′-Chlorobiphenyl-4-ylmethyl)-[4-(2H-tetrazol-5-yl)-phenyl]-amine

HPLC-MS (Method D): m/z: 362 (M+1); Rt=5.30 min.

General Procedure (I) for Preparation of Compounds of General FormulaI₈:

wherein K, M and T are as defined above.

This procedure is very similar to general procedure (A), the onlydifference being the carboxylic acid is containing a tetrazole moiety.When the acylation is complete, the product is isolated by extraction,filtration, chromatography or other methods known to those skilled inthe art.

The general procedure (I) is further illustrated in the followingexample 690:

Example 690 General Procedure (I)4-[4-(2H-Tetrazol-5-yl)benzoylamino]benzoic acid

To a solution of 4-(2H-tetrazol-5-yl)benzoic acid (example 605, 4 mmol)and HOAt (4.2 mmol) in DMF (6 mL) was added1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (4.2 mmol)and the resulting mixture was stirred at room temperature for 1 hour. Analquot of this HOAt-ester solution (0.45 mL) was mixed with 0.25 mL of asolution of 4-aminobenzoic acid (1.2 mmol in 1 mL DMF). (Anilines ashydrochlorides can also be utilised, a slight excess of triethylaminewas added to the hydrochloride suspension in DMF prior to mixing withthe HOAt-ester.) The resulting mixture was shaken for 3 days at roomtemperature. 1 N hydrochloric acid (2 mL) was added and the mixture wasshaken for 16 hours at room temperature. The solid was isolated bycentrifugation (alternatively by filtration or extraction) and waswashed with water (3 mL). Drying in vacuo at 40° C. for 2 days affordedthe title compound.

HPLC-MS (Method D): m/z: 310 (M+1); Rt=2.83 min.

Example 691 General Procedure (I)3-[4-(2H-Tetrazol-5-yl)benzoylamino]benzoic acid

HPLC-MS (Method D): m/z: 310 (M+1); Rt=2.89 min.

Example 692 General Procedure (I)3-{4-[4-(2H-Tetrazol-5-yl)benzoylamino]phenyl}acrylic acid

HPLC-MS (Method D): m/z: 336 (M+1); Rt=3.10 min.

Example 693 General Procedure (I)3-{4-[4-(2H-Tetrazol-5-yl)benzoylamino]phenyl}propionic acid

HPLC-MS (Method D): m/z: 338 (M+1); Rt=2.97 min.

Example 694 General Procedure (I)3-Methoxy-4-[4-(2H-tetrazol-5-yl)benzoylamino]benzoic acid

HPLC-MS (Method D): m/z: 340 (M+1); Rt=3.03 min.

Example 695 General Procedure (I)N-(4-Benzyloxyphenyl)-4-(2H-tetrazol-5-yl)benzamide

HPLC-MS (Method D): m/z: 372 (M+1); Rt=4.47 min.

Example 696 General Procedure (I)N-(4-Phenoxyphenyl)-4-(2H-tetrazol-5-yl)benzamide

HPLC-MS (Method D): m/z: 358 (M+1); Rt=4.50 min.

Example 697 General Procedure (I)N-(9H-Fluoren-2-yl)-4-(2H-tetrazol-5-yl)benzamide

HPLC-MS (Method D): m/z: 354 (M+1); Rt=4.60 min.

Example 698 General Procedure (I)N-(9-Ethyl-9H-carbazol-2-yl)-4-(2H-tetrazol-5-yl)benzamide

HPLC-MS (Method D): m/z: 383 (M+1); Rt=4.60 min.

Example 699 General Procedure (I) N-Phenyl-4-(2H-tetrazol-5-yl)benzamide

HPLC-MS (Method D): m/z: 266 (M+1); Rt=3.23 min.

Example 700 General Procedure (I)4-[4-(2H-Tetrazol-5-ylmethoxy)benzoylamino]benzoic acid

The starting material was prepared as described in example 592.

HPLC-MS (Method D): m/z: 340 (M+1); Rt=2.83 min.

Example 701 General Procedure (I)3-[4-(2H-Tetrazol-5-ylmethoxy)benzoylamino]benzoic acid

HPLC-MS (Method D): m/z: 340 (M+1); Rt=2.90 min.

Example 702 General Procedure (I)3-{4-[4-(2H-Tetrazol-5-ylmethoxy)benzoylamino]phenyl}acrylic acid

HPLC-MS (Method D): m/z: 366 (M+1); Rt=3.07 min.

Example 703 General Procedure (I)3-{4-[4-(2H-Tetrazol-5-ylmethoxy)benzoylamino]phenyl}propionic acid

HPLC-MS (Method D): m/z: 368 (M+1); Rt=2.97 min.

Example 704 General Procedure (I)3-Methoxy-4-[4-(2H-tetrazol-5-ylmethoxy)benzoylamino]benzoic acid

HPLC-MS (Method D): m/z: 370 (M+1); Rt=3.07 min.

Example 705 General Procedure (I)N-(4-Benzyloxyphenyl)-4-(2H-tetrazol-5-ylmethoxy)benzamide

HPLC-MS (Method D): m/z: 402 (M+1); Rt=4.43 min.

Example 706 General Procedure (I)N-(4-Phenoxyphenyl)-4-(2H-tetrazol-5-ylmethoxy)benzamide

HPLC-MS (Method D): m/z: 388 (M+1); Rt=4.50 min.

Example 707 General Procedure (I)N-(9H-Fluoren-2-yl)-4-(2H-tetrazol-5-ylmethoxy)benzamide

HPLC-MS (Method D): m/z: 384 (M+1); Rt=4.57 min.

Example 708 General Procedure (I)N-(9-Ethyl-9H-carbazol-2-yl)-4-(2H-tetrazol-5-ylmethoxy)benzamide

HPLC-MS (Method D): m/z: 413 (M+1); Rt=4.57 min.

Example 709 General Procedure (I)N-Phenyl-4-(2H-tetrazol-5-ylmethoxy)benzamide

HPLC-MS (Method D): m/z: 296 (M+1); Rt=3.23 min.

Example 710 General Procedure (I)4-[4-(2H-Tetrazol-5-ylmethylsulfanyl)benzoylamino]benzoic acid

The starting material was prepared as described in example 593.

HPLC-MS (Method D): m/z: 356 (M+1); Rt=2.93 min.

Example 711 General Procedure (I)3-[4-(2H-Tetrazol-5-ylmethylsulfanyl)benzoylamino]benzoic acid

HPLC-MS (Method D): m/z: 356 (M+1); Rt=3.00 min.

Example 712 General Procedure (I)3-{4-[4-(2H-Tetrazol-5-ylmethylsulfanyl)benzoylamino]phenyl}acrylic acid

HPLC-MS (Method D): m/z: 382 (M+1); Rt=3.26 min.

Example 713 General Procedure (I)3-{4-[4-(2H-Tetrazol-5-ylmethylsulfanyl)benzoylamino]phenyl}propionicacid

HPLC-MS (Method D): m/z: 384 (M+1); Rt=3.10 min.

Example 714 General Procedure (I)3-Methoxy-4-[4-(2H-tetrazol-5-ylmethylsulfanyl)benzoylamino]benzoic acid

HPLC-MS (Method D): m/z: 386 (M+1); Rt=3.20 min.

Example 715 General Procedure (I)N-(4-Benzyloxyphenyl)-4-(2H-tetrazol-5-ylmethylsulfanyl)benzamide

HPLC-MS (Method D): m/z: 418 (M+1); Rt=4.57 min.

Example 716 General Procedure (I)N-(4-Phenoxyphenyl)-4-(2H-tetrazol-5-ylmethylsulfanyl)benzamide

HPLC-MS (Method D): m/z: 404 (M+1); Rt=4.60 min.

Example 717 General Procedure (I)N-(9H-Fluoren-2-yl)-4-(2H-tetrazol-5-ylmethylsulfanyl)benzamide

HPLC-MS (Method D): m/z: 400 (M+1); Rt=4.67 min.

Example 718 General Procedure (I)N-(9-Ethyl-9H-carbazol-2-yl)-4-(2H-tetrazol-5-ylmethylsulfanyl)benzamide

HPLC-MS (Method D): m/z: 429 (M+1); Rt=4.67 min.

Example 719 General Procedure (I)N-Phenyl-4-(2H-tetrazol-5-ylmethylsulfanyl)benzamide

HPLC-MS (Method D): m/z: 312 (M+1); Rt=3.40 min.

General Procedure (J) for Solution Phase Preparation of Amides ofGeneral Formula I₉:

wherein T is as defined above.

This general procedure (J) is further illustrated in the followingexample.

Example 720 General Procedure (J)9-(3-Chlorobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

3-(2H-Tetrazol-5-yl)-9H-carbazole (example 594, 17 g, 72.26 mmol) wasdissolved in N,N-dimethylformamide (150 mL). Triphenylmethyl chloride(21.153 g, 75.88 mmol) and triethylamine (20.14 mL, 14.62 g, 144.50mmol) were added consecutively. The reaction mixture was stirred for 18hours at room temperature, poured into water (1.5 L) and stirred for anadditional 1 hour. The crude product was filtered off and dissolved indichloromethane (500 mL). The organic phase was washed with water (2×250mL) and dried with magnesium sulfate (1 h). Filtration followed byconcentration yielded a solid which was triturated in heptanes (200 mL).Filtration furnished3-[2-(triphenylmethyl)-2H-tetrazol-5-yl]-9H-carbazole (31.5 g) which wasused without further purification.

¹H-NMR (CDCl₃): δ8.87 (1H, d), 8.28 (1H, bs), 8.22 (1H, dd), 8.13 (1H,d), 7.49 (1H, d), 7.47-7.19 (18H, m); HPLC-MS (Method C): m/z: 243(triphenylmethyl); Rt=5.72 min.

3-[2-(Triphenylmethyl)-2H-tetrazol-5-yl]-9H-carbazole (200 mg, 0.42mmol) was dissolved in methyl sulfoxide (1.5 mL). Sodium hydride (34 mg,60%, 0.85 mmol) was added, and the resulting suspension was stirred for30 min at room temperature. 3-Chlorobenzyl chloride (85 μL, 108 mg, 0.67mmol) was added, and the stirring was continued at 40° C. for 18 hours.The reaction mixture was cooled to ambient temperature and poured into0.1 N hydrochloric acid (aq.) (15 mL). The precipitated solid wasfiltered off and washed with water (3×10 mL) to furnish9-(3-chlorobenzyl)-3-[2-triphenylmethyl)-2H-tetrazol-5-yl]-9H-carbazole,which was dissolved in a mixture of tetrahydrofuran and 6 N hydrochloricacid (aq.) (9:1) (10 mL) and stirred at room temperature for 18 hours.The reaction mixture was poured into water (100 mL). The solid wasfiltered off and rinsed with water (3×10 mL) and dichloromethane (3×10mL) to yield the title compound (127 mg). No further purification wasnecessary.

¹H-NMR (DMSO-d₆): δ8.89 (1H, d), 8.29 (1H, d), 8.12 (1H, dd), 7.90 (1H,d), 7.72 (1H, d), 7.53 (1H, t), 7.36-7.27 (4H, m), 7.08 (1H, bt), 5.78(2H, s); HPLC-MS (Method B): m/z: 360 (M+1); Rt=5.07 min.

The compounds in the following examples were prepared in a similarfashion. Optionally, the compounds can be further purified byrecrystallization from e.g. aqueous sodium hydroxide (1 N) or bychromatography.

Example 721 General Procedure (J)9-(4-Chlorobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 360 (M+1); Rt=4.31 min.

Example 722 General Procedure (J)9-(4-Methylbenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 340 (M+1); Rt=4.26 min.

Example 723 General Procedure (J)3-(2H-Tetrazol-5-yl)-9-(4-trifluoromethylbenzyl)-9H-carbazole

HPLC-MS (Method C): m/z: 394 (M+1); Rt=4.40 min.

Example 724 General Procedure (J)9-(4-Benzyloxybenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 432 (M+1); Rt=4.70 min.

Example 725 General Procedure (J)9-(3-Methylbenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 340 (M+1); Rt=4.25 min.

Example 726 General Procedure (J)9-Benzyl-3-(2H-tetrazol-5-yl)-9H-carbazole

¹H-NMR (DMSO-d₆): δ8.91 (1H, dd), 8.30 (1H, d), 8.13 (1H, dd), 7.90 (1H,d), 7.73 (1H, d), 7.53 (1H, t), 7.36-7.20 (6H, m), 5.77 (2H, s).

Example 727 General Procedure (J)9-(4-Phenylbenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

¹H-NMR (DMSO-d₆): δ8.94 (1H, s), 8.33 (1H, d), 8.17 (1H, dd), 7.95 (1H,d), 7.77 (1H, d), 7.61-7.27 (11H, m), 5.82 (2H, s).

Example 728 General Procedure (J)9-(3-Methoxybenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 356 (M+1); Rt=3.99 min.

Example 729 General Procedure (J)9-(Naphthalen-2-ylmethyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 376 (M+1); Rt=4.48 min.

Example 730 General Procedure (J)9-(3-Bromobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 404 (M+1); Rt=4.33 min.

Example 731 General Procedure (J)9-(Biphenyl-2-ylmethyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 402 (M+1); Rt=4.80 min.

Example 732 General Procedure (J)3-(2H-Tetrazol-5-yl)-9-[4-(1,2,3-thiadiazol-4-yl)benzyl]-9H-carbazole

Example 733 General Procedure (J)9-(2′-Cyanobiphenyl-4-ylmethyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

¹H-NMR (DMSO-d₆): δ8.91 (1H, d), 8.31 (1H, d), 8.13 (1H, dd), 7.95 (1H,d), 7.92 (1H, d), 7.78 (1H, d), 7.75 (1H, dt), 7.60-7.47 (5H, m),7.38-7.28 (3H, m), 5.86 (2H, s); HPLC-MS (Method C): m/z: 427 (M+1);Rt=4.38 min.

Example 734 General Procedure (J)9-(4-Iodobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 452 (M+1); Rt=4.37 min.

Example 735 General Procedure (J)9-(3,5-Bis(trifluoromethyl)benzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 462 (M+1); Rt=4.70 min.

Example 736 General Procedure (J)9-(4-Bromobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

¹H-NMR (DMSO-d₆): δ8.89 (1H, d), 8.29 (1H, d), 8.11 (1H, dd), 7.88 (1H,d), 7.70 (1H, d), 7.52 (1H, t), 7.49 (2H, d), 7.31 (1H, t), 7.14 (2H,d), 5.74 (2H, s); HPLC-MS (Method C): m/z: 404 (M+1); Rt=4.40 min.

Example 737 General Procedure (J)9-(Anthracen-9-ylmethyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 426 (M+1); Rt=4.78 min.

Example 738 General Procedure (J)9-(4-Carboxybenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

3.6 fold excess sodium hydride was used.

¹H-NMR (DMSO-d₆): δ12.89 (1H, bs), 8.89 (1H, d), 8.30 (1H, d), 8.10 (1H,dd), 7.87 (1H, d), 7.86 (2H, d), 7.68 (1H, d), 7.51 (1H, t), 7.32 (1H,t), 7.27 (2H, d), 5.84 (2H, s); HPLC-MS (Method C): m/z: 370 (M+1);Rt=3.37 min.

Example 739 General Procedure (J)9-(2-Chlorobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method B): m/z: 360 (M+1); Rt=5.30 min.

Example 740 General Procedure (J)9-(4-Fluorobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

¹H-NMR (DMSO-d₆): δ8.88 (1H, d), 8.28 (1H, d), 8.10 (1H, dd), 7.89 (1H,d), 7.72 (1H, d), 7.52 (1H, t), 7.31 (1H, t), 7.31-7.08 (4H, m), 5.74(2H, s); HPLC-MS (Method C): m/z: 344 (M+1); Rt=4.10 min.

Example 741 General Procedure (J)9-(3-Fluorobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

¹H-NMR (DMSO-d₆): δ8.89 (1H, d), 8.29 (1H, d), 8.12 (1H, dd), 7.90 (1H,d), 7.72 (1H, d), 7.53 (1H, t), 7.37-7.27 (2H, m), 7.12-7.02 (2H, m),6.97 (1H, d), 5.78 (2H, s); HPLC-MS (Method C): m/z: 344 (M+1); Rt=4.10min.

Example 742 General Procedure (J)9-(2-Iodobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 452 (M+1); Rt=4.58 min.

Example 743 General Procedure (J)9-(3-Carboxybenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

3.6 fold excess sodium hydride was used.

¹H-NMR (DMSO-d₆): δ12.97 (1H, bs), 8.90 (1H, bs), 8.30 (1H, d), 8.12(1H, bd), 7.89 (1H, d), 7.82 (1H, m), 7.77 (1H, bs), 7.71 (1H, d), 7.53(1H, t), 7.46-7.41 (2H, m), 7.32 (1H, t), 5.84 (2H, s); HPLC-MS (MethodC): m/z: 370 (M+1); Rt=3.35 min.

Example 744 General Procedure (J)9-[4-(2-Propyl)benzyl]-3-(2H-tetrazol-5-yl)-9H-carbazole

¹H-NMR (DMSO-d₆): δ8.87 (1H, d), 8.27 (1H, d), 8.10 (1H, dd), 7.87 (1H,d), 7.71 (1H, d), 7.51 (1H, t), 7.31 (1H, t), 7.15 (2H, d), 7.12 (2H,d), 5.69 (2H, s), 2.80 (1h, sept), 1.12 (6H, d); HPLC-MS (Method C):m/z: 368 (M+1); Rt=4.73 min.

Example 745 General Procedure (J)9-(3,5-Dimethoxybenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 386 (M+1); Rt=4.03 min.

Example 746 General Procedure (J)3-(2H-Tetrazol-5-yl)-9-(2,4,5-trifluorobenzyl)-9H-carbazole

HPLC-MS (Method B): m/z: 380 (M+1); Rt=5.00 min.

Example 747 General Procedure (J)N-Methyl-N-phenyl-2-[3-(2H-tetrazol-5-yl)carbazol-9-yl]acetamide

HPLC-MS (Method B): m/z: 383 (M+1); Rt=4.30 min.

Example 748 General Procedure (J)9-(4-Methoxybenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

¹H-NMR (DMSO-d₆): δ8.86 (1H, d), 8.26 (1H, d), 8.10 (1H, dd), 7.90 (1H,d), 7.73 (1H, d), 7.51 (1H, t), 7.30 (1H, t), 7.18 (2H, d), 6.84 (2H,d), 5.66 (2H, s), 3.67 (3H, s); HPLC-MS (Method B): m/z: 356 (M+1);Rt=4.73 min.

Example 749 General Procedure (J)9-(2-Methoxybenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

¹H-NMR (DMSO-d₆): δ8.87 (1H, d), 8.27 (1H, d), 8.09 (1H, dd), 7.77 (1H,d), 7.60 (1H, d), 7.49 (1H, t), 7.29 (1H, t), 7.23 (1H, bt), 7.07 (1H,bd), 6.74 (1H, bt), 6.61 (1H, bd), 5.65 (2H, s), 3.88 (3H, s); HPLC-MS(Method B): m/z: 356 (M+1); Rt=4.97 min.

Example 750 General Procedure (J)9-(4-Cyanobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 351 (M+1); Rt=3.74 min.

Example 751 General Procedure (J)9-(3-Cyanobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 351 (M+1); Rt=3.73 min.

Example 752 General Procedure (J)9-(5-Chloro-2-methoxybenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

¹H-NMR (DMSO-d₆): δ8.87 (1H, d), 8.35 (1H, d), 8.10 (1H, dd), 7.73 (1H,d), 7.59 (1H, d), 7.49 (1H, t), 7.29 (1H, t), 7.27 (1H, dd), 7.11 (1H,d), 6.51 (1H, d), 5.63 (2H, s), 3.88 (3H, s); HPLC-MS (Method C): m/z:390 (M+1); Rt=4.37 min.

Example 753 General Procedure (J)N-Phenyl-2-[3-(2H-tetrazol-5-yl)carbazol-9-yl]acetamide

¹H-NMR (DMSO-d₆): δ10.54 (1H, s), 8.87 (1H, bs), 8.27 (1H, d), 8.12 (1H,bd), 7.83 (1H, d), 7.66 (1H, d), 7.61 (2H, d), 7.53 (1H,t), 7.32 (1H,t), 7.32 (2H, t), 7.07 (1H, t), 5.36 (2H, s); HPLC-MS (Method C): m/z:369 (M+1); Rt=3.44 min.

Example 754 General Procedure (J)N-Butyl-2-[3-(2H-tetrazol-5-yl)carbazol-9-yl]acetamide

¹H-NMR (DMSO-d₆): δ8.85 (1H, d), 8.31 (1H, t), 8.25 (1H, d), 8.10 (1H,dd), 7.75 (1H, d), 7.58 (1H, d), 7.52 (1H, t), 7.30 (1H, t), 5.09 (2H,s), 3.11 (2H, q), 1.42 (2H, quint), 1.30 (2H, sext), 0.87 (3H, t);HPLC-MS (Method C): m/z: 349 (M+1); Rt=3.20 min.

Example 755 General Procedure (J)9-(2,4-Dichlorobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

¹H-NMR (DMSO-d₆): δ8.92 (1H, d), 8.32 (1H, d), 8.09 (1H, dd), 7.76 (1H,d), 7.74 (1H, d), 7.58 (1H, d), 7.51 (1H, t), 7.33 (1H, t), 7.23 (1H,dd), 6.42 (1H, d), 5.80 (2H, s); HPLC-MS (Method B): m/z: 394 (M+1);Rt=5.87 min.

Example 756 General Procedure (J)9-(2-Methylbenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

¹H-NMR (DMSO-d₆): δ8.92 (1H, d), 8.32 (1H, d), 8.08 (1H, dd), 7.72 (1H,d), 7.55 (1H, d), 7.48 (1H, t), 7.32 (1H, t), 7.26 (1H, d), 7.12 (1H,t), 6.92 (1H, t), 6.17 (1H, d), 5.73 (2H, s), 2.46 (3H, s); HPLC-MS(Method B): m/z: 340 (M+1); Rt=5.30 min.

Example 757 General Procedure (J)9-(3-Nitrobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 371 (M+1); Rt=3.78 min.

Example 758 General Procedure (J)9-(3,4-Dichlorobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method B): m/z: 394 (M+1); Rt=5.62 min.

Example 759 General Procedure (J)9-(2,4-Difluorobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

¹H-NMR (DMSO-d₆): δ8.89 (1H, d), 8.29 (1H, d), 8.11 (1H, dd), 7.88 (1H,d), 7.69 (1H, d), 7.52 (1H, t), 7.36-7.24 (2H, m), 7.06-6.91 (2H, m),5.78 (2H, s); HPLC-MS (Method B): m/z: 362 (M+1); Rt=5.17 min.

Example 760 General Procedure (J)9-(3,5-Difluorobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

¹H-NMR (DMSO-d₆): δ8.90 (1H, bs), 8.31 (1H, d), 8.13 (1H, bd), 7.90 (1H,d), 7.73 (1H, d), 7.54 (1H, t), 7.34 (1H, t), 7.14 (1H, t), 6.87 (2H,bd), 5.80 (2H, s); HPLC-MS (Method B): m/z: 362 (M+1); Rt=5.17 min.

Example 761 General Procedure (J)9-(3,4-Difluorobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

¹H-NMR (DMSO-d₆): δ8.89 (1H, bs), 8.29 (1H, d), 8.12 (1H, bd), 7.92 (1H,d), 7.74 (1H, d), 7.54 (1H, t), 7.42-7.25 (3H, m), 6.97 (1H, bm), 5.75(2H, s); HPLC-MS (Method B): m/z: 362 (M+1); Rt=5.17 min.

Example 762 General Procedure (J)9-(3-Iodobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method B): m/z: 452 (M+1); Rt=5.50 min.

Example 763 General Procedure (J)3-(2H-Tetrazol-5-yl)-9-[3-(trifluoromethyl)benzyl]-9H-carbazole

¹H-NMR (DMSO-d₆): δ8.89 (1H, d), 8.30 (1H, d), 8.11 (1H, dd), 7.90 (1H,d), 7.72 (1H, d), 7.67 (1H, bs), 7.62 (1H, bd), 7.53 (1H, t), 7.50 (1H,bt), 7.33 (1H, bd), 7.32 (1H, t), 5.87 (2H, s); HPLC-MS (Method B): m/z:394 (M+1); Rt=5.40 min.

Example 764 General Procedure (J)N-(4-Carboxyphenyl)-2-[3-(2H-tetrazol-5-yl)carbazol-9-yl]acetamide

3.6 fold excess sodium hydride was used.

HPLC-MS (Method B): m/z: 413 (M+1); Rt=3.92 min.

Example 765 General Procedure (J)N-(2-Propyl)-2-[3-(2H-tetrazol-5-yl)carbazol-9-yl]acetamide

HPLC-MS (Method B): m/z: 335 (M+1); Rt=3.70 min.

Example 766 General Procedure (J)N-Benzyl-N-phenyl-2-[3-(2H-tetrazol-5-yl)carbazol-9-yl]acetamide

HPLC-MS (Method B): m/z: 459 (M+1); Rt=5.37 min.

Example 767 General Procedure (J)N-[4-(2-Methyl-2-propyl)phenyl]-2-[3-(2H-tetrazol-5-yl)carbazol-9-yl]acetamide

HPLC-MS (Method B): m/z: 425 (M+1); Rt=5.35 min.

Example 768 General Procedure (J)N-Phenethyl-2-[3-(2H-tetrazol-5-yl)carbazol-9-yl]acetamide

HPLC-MS (Method C): m/z: 397 (M+1); Rt=3.43 min.

Example 769 General Procedure (J)3-(2H-Tetrazol-5-yl)-9-[2-(trifluoromethyl)benzyl]-9H-carbazole

HPLC-MS (Method C): m/z: 394 (M+1); Rt=4.44 min.

Example 770 General Procedure (J)9-[2-Fluoro-6-(trifluoromethyl)benzyl]-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 412 (M+1); Rt=4.21 min.

Example 771 General Procedure (J)9-[2,4-Bis(trifluoromethyl)benzyl)]-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 462 (M+1); Rt=4.82 min.

Example 772 General Procedure (J)3-(2H-Tetrazol-5-yl)-9-(2,4,6-trimethylbenzyl)-9H-carbazole

HPLC-MS (Method C): m/z: 368 (M+1); Rt=4.59 min.

Example 773 General Procedure (J)9-(2,3,5,6-Tetramethylbenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 382 (M+1); Rt=4.47 min.

Example 774 General Procedure (J)9-[(Naphthalen-1-yl)methyl]-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 376 (M+1); Rt=4.43 min.

Example 775 General Procedure (J)9-[Bis(4-fluorophenyl)methyl]-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 438 (M+1); Rt=4.60 min.

Example 776 General Procedure (J)9-(2-Bromobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 404 (M+1); Rt=4.50 min.

Example 777 General Procedure (J)9-(2-Fluorobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 344 (M+1); Rt=4.09 min.

Example 778 General Procedure (J)9-(4-Carboxy-2-methylbenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

In this preparation, a 3.6-fold excess of sodium hydride was used.

HPLC-MS (Method C): m/z: 384 (M+1); Rt=3.56 min.

Example 779 General Procedure (J)9-(2-Phenylethyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 340 (M+1); Rt=4.08 min.

Example 780 General Procedure (J)9-[2-Fluoro-5-(trifluoromethyl)benzyl]-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 412 (M+1); Rt=4.34 min.

Example 781 General Procedure (J)9-(4-Carboxy-2-fluorobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

3-Fluoro-4-methylbenzoic acid (3.0 g, 19.5 mmol) and benzoyl peroxide(0.18 g, 0.74 mmol) were suspended in benzene. The mixture was purgedwith N₂ and heated to reflux. N-Bromosuccinimide (3.47 g, 19.5 mmol) wasadded portionwise, and reflux was maintained for 18 hours. The reactionmixture was concentrated, and the residue was washed with water (20 mL)at 70° C. for 1 hour. The crude product was isolated by filtration andwashed with additional water (2×10 mL). The dry product wasrecrystallized from heptanes. Filtration furnished4-bromomethyl-3-fluorobenzoic acid (1.92 g) which was used in thefollowing step according to General Procedure (J).

In this preparation, a 3.6-fold excess of sodium hydride was used.

HPLC-MS (Method C): m/z: 388 (M+1); Rt=3.49 min.

Example 782 General Procedure (J)5-{4-[[(3-(2H-Tetrazol-5-yl)carbazol-9-yl)methyl]naphthalen-1-yl]oxy}pentanoicAcid

5-[(4-Formylnaphthalen-1-yl)oxy]pentanoic acid intermediate obtained inexample 470(3.0 g, 11.0 mmol) was dissolved in a mixture of methanol andtetrahydrofuran (9:1) (100 mL), and sodium borohydride (1.67 g, 44.1mmol) was added portionwise at ambient temperature. After 30 minutes,the reaction mixture was concentrated to 50 mL and added to hydrochloricacid (0.1 N, 500 mL). Additional hydrochloric acid (1 N, 40 mL) wasadded, and 5-[(4-hydroxymethyl-naphthalen-1-yl)oxy]pentanoic acid (2.90g) was collected by filtration. To the crude product was addedconcentrated hydrochloric acid (100 mL), and the suspension was stirredvigorously for 48 hours at room temperature. The crude product wasfiltered off and washed with water, until the pH was essentiallyneutral. The material was washed with heptanes to furnish5-[(4-chloromethylnaphthalen-1-yl)oxy]pentanoic acid (3.0 g) which wasused in the following step according to General Procedure (J).

In this preparation, a 3.6-fold excess of sodium hydride was used.

HPLC-MS (Method C): m/z: 492 (M+1); Rt=4.27 min.

Example 783 General Procedure (J)9-(2,3-Difluorobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z=362 (M+1); Rt=4.13 min.

Example 784 General Procedure (J)9-(2,5-Difluorobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z=362 (M+1); Rt=4.08 min.

Example 785 General Procedure (J)9-Pentafluorophenylmethyl-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z=416 (M+1); Rt=4.32 min.

Example 786 General Procedure (J)9-(2,6-Difluorobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z=362 (M+1); Rt=3.77 min.

Further compounds of the invention that may be prepared according togeneral procedure (J), and includes: Example 787

Example 788

Example 789

Example 790

Example 791

Example 792

Example 793

Example 794

Example 795

Example 796

Example 797

Example 798

Example 799

The following compounds of the invention may be prepared eg. from9-(4-bromobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole (example 736) orfrom 9-(3-bromobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole (example 730)and aryl boronic acids via the Suzuki coupling reaction eg as describedin Littke, Dai & Fu J. Am. Chem. Soc., 2000, 122, 4020-8 (or referencescited therein), or using the methodology described in general procedure(E), optionally changing the palladium catalyst tobis(tri-tert-butylphosphine)palladium (0). Example 800

Example 801

Example 802

Example 803

Example 804

Example 805

General Procedure (K) for Preparation of Compounds of General FormulaI₁₀:

wherein T is as defined above.

The general procedure (K) is further illustrated by the followingexample:

Example 806 General Procedure (K)1-Benzyl-5-(2H-tetrazol-5-yl)-1H-indole

5-Cyanoindole (1.0 g, 7.0 mmol) was dissolved in N,N-dimethylformamide(14 mL) and cooled in an ice-water bath. Sodium hydride (0.31 g, 60 %,7.8 mmol) was added, and the resulting suspension was stirred for 30min. Benzyl chloride (0.85 mL, 0.94 g, 7.4 mmol) was added, and thecooling was discontinued. The stirring was continued for 65 hours atroom temperature. Water (150 mL) was added, and the mixture wasextracted with ethyl acetate (3×25 mL). The combined organic phases werewashed with brine (30 mL) and dried with sodium sulfate (1 hour).Filtration and concentration yielded the crude material. Purification byflash chromatography on silica gel eluting with ethylacetate/heptanes=1:3 afforded 1.60 g 1-benzyl-1H-indole-5-carbonitrile.

HPLC-MS (Method C): m/z: 233 (M+1); Rt=4.17 min.

1-Benzyl-1H-indole-5-carbonitrile was transformed into1-benzyl-5-(2H-tetrazol-5-yl)-1H-indole by the method described ingeneral procedure (J) and in example 594. Purification was done by flashchromatography on silica gel eluting with dichloromethane/methanol=9:1.

HPLC-MS (Method C): m/z: 276 (M+1); Rt=3.35 min.

The compounds in the following examples were prepared by the sameprocedure.

Example 807 General Procedure (K)1-(4-Bromobenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method C): m/z: 354 (M+1); Rt=3.80 min.

Example 808 General Procedure (K)1-(4-Phenylbenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

¹H-NMR (200 MHz, DMSO-d₆): δ=5.52 (2H, s), 6.70 (1H, d), 7.3-7.45 (6H,m), 7.6 (4H, m), 7.7-7.8 (2H, m), 7.85(1H, dd), 8.35 (1H, d). Calculatedfor C₂₂H₁₇N₅, H₂O: 73.32% C; 5.03% H; 19.43% N. Found: 73.81% C; 4.90%H; 19.31% N.

Example 8094′-[5-(2H-Tetrazol-5-yl)indol-1-ylmethyl]biphenyl-4-carboxylic acid

5-(2H-Tetrazol-5-yl)-1H-indole (Syncom BV, Groningen, NL) (1.66 g, 8.9mmol) was treated with trityl chloride (2.5 g, 8.9 mmol) and triethylamine (2.5 mL, 17.9 mmol) in DMF(25 mL) by stirring at RT overnight. Theresulting mixture was treated with water. The gel was isolated,dissolved in methanol, treated with activated carbon; filtered andevaporated to dryness in vacuo. This afforded 3.6 g (94%) of crude5-(2-trityl-2H-tetrazol-5-yl)-1H-indole.

HPLC-MS (Method C): m/z=450 (M+23); Rt.=5.32 min.

4-Methylphenylbenzoic acid (5 g, 23.5 mmol) was mixed with CCl₄ (100 mL)and under an atmosphere of nitrogen, the slurry was addedN-Bromosuccinimide (4.19 g, 23.55 mmol) and dibenzoyl peroxide (0.228 g,0.94 mmol). The mixture was subsequently heated to reflux for 0.5 hour.After cooling, DCM and water (each 30 mL) were added. The resultingprecipitate was isolated, washed with water and a small amount ofmethanol. The solid was dried in vacuo to afford 5.27 g (77%) of4′-bromomethylbiphenyl-4-carboxylic acid.

HPLC-MS (Method C): m/z=291 (M+1); Rt.=3.96 min.

5-(2-Trityl-2H-tetrazol-5-yl)-1H-indole (3.6 g, 8.4 mmol) was dissolvedin DMF (100 mL). Under nitrogen, NaH (60% suspension in mineral oil, 34mmol) was added slowly. 4′-Bromomethylbiphenyl-4-carboxylic acid (2.7 g,9.2 mmol) was added over 5 minutes and the resulting slurry was heatedat 40° C. for 16 hours. The mixture was poured into water (100 mL) andthe precipitate was isolated by filtration and treated with THF/6N HCl(9/1) (70 mL) at room temperature for 16 hours. The mixture wassubsequently evaporated to dryness in vacuo, the residue was treatedwith water and the solid was isolated by filtration and washedthoroughly 3 times with DCM. The solid was dissolved in hot THF (400 mL)treated with activated carbon and filtered. The filtrate was evaporatedin vacuo to dryness. This afforded 1.6 g (50%) of the title compound.

HPLC-MS (Method C): m/z=396 (M+1); Rt.=3.51 min.

Example 810 General Procedure (K) 5-(2H-Tetrazol-5-yl)-1H-indole

5-(2H-Tetrazol-5-yl)-1H-indole was prepared from 5-cyanoindole accordingto the method described in example 594.

HPLC-MS (Method C): m/z: 186 (M+1); Rt=1.68 min.

Example 811 General Procedure (K)1-Benzyl-4-(2H-tetrazol-5-yl)-1H-indole

1-Benzyl-1H-indole-4-carbonitrile was prepared from 4-cyanoindoleaccording to the method described in example 806.

HPLC-MS (Method C): m/z: 233 (M+1); Rt=4.24 min.

1-Benzyl-4-(2H-tetrazol-5-yl)-1H-indole was prepared from1-benzyl-1H-indole-4-carbonitrile according to the method described inexample 594.

HPLC-MS (Method C): m/z: 276 (M+1); Rt=3.44 min.

General Procedure (L) for Preparation of Compounds of General FormulaI₁₁:

wherein T is as defined above and

-   -   Pol—is a polystyrene resin loaded with a 2-chlorotrityl linker,        graphically shown below:

This general procedure (L) is further illustrated by the followingexample:

Example 812 General Procedure (L)5-(2H-Tetrazol-5-yl)-1-[3-(trifluoromethyl)benzyl]-1H-indole

2-Chlorotritylchloride resin (100 mg, 0.114 mmol active chloride) wasswelled in dichloromethane (2 mL) for 30 min. The solvent was drained,and a solution of 5-(2H-tetrazol-5-yl)-1H-indole (example 810) (63 mg,0.34 mmol) in a mixture of N,N-dimethylformamide, dichloromethane andN,N-di(2-propyl)ethylamine (DIPEA) (5:5:2) (1.1 mL) was added. Thereaction mixture was shaken at room temperature for 20 hours. Thesolvent was removed by filtration, and the resin was washedconsecutively with N,N-dimethylformamide (2×4 mL), dichloromethane (6×4mL) and methyl sulfoxide (2×4 mL). Methyl sulfoxide (1 mL) was added,followed by the addition of a solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.0 M, 0.57 mL, 0.57 mmol).The mixture was shaken for 30 min at room temperature, before3-(trifluoromethyl)benzyl bromide (273 mg, 1.14 mmol) was added as asolution in methyl sulfoxide (0.2 mL). The reaction mixture was shakenfor 20 hours at room temperature. The drained resin was washedconsecutively with methyl sulfoxide (2×4 mL), dichloromethane (2×4 mL),methanol (2×4 mL), dichloromethane (2×4 mL) and tetrahydrofuran (4 mL).The resin was treated with a solution of hydrogen chloride intetrahydrofuran, ethyl ether and ethanol=8:1:1 (0.1 M, 3 mL) for 6 hoursat room temperature. The resin was drained and the filtrate wasconcentrated in vacuo. The crude product was re-suspended indichloromethane (1.5 mL) and concentrated three times to afford thetitle compound (35 mg). No further purification was necessary.

HPLC-MS (Method B): m/z: 344 (M+1); Rt=4.35 min. ¹H-NMR (DMSO-d₆): δ8.29(1H, s), 7.80 (1H, dd), 7.72 (2H, m), 7.64 (2H, bs), 7.56 (1H, t), 7.48(1H, d), 6.70 (1H, d), 5.62 (2H, s).

The compounds in the following examples were prepared in a similarfashion. Optionally, the compounds can be further purified byrecrystallization or by chromatography.

Example 813 General Procedure (L)1-(4-Chlorobenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 310 (M+1); Rt=4.11 min.

Example 814 General Procedure (L)1-(2-Chlorobenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 310 (M+1); Rt=4.05 min.

Example 815 General Procedure (L)1-(4-Methoxybenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 306 (M+1); Rt=3.68 min.

Example 816 General Procedure (L)1-(4-Methylbenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 290 (M+1); Rt=3.98 min.

Example 817 General Procedure (L)5-(2H-Tetrazol-5-yl)-1-[4-(trifluoromethyl)benzyl]-1H-indole

HPLC-MS (Method B): m/z: 344 (M+1); Rt=4.18 min.

Example 818 General Procedure (L)1-(3-Chlorobenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 310 (M+1); Rt=4.01 min.

Example 819 General Procedure (L)1-(3-Methylbenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 290 (M+1); Rt=3.98 min.

Example 820 General Procedure (L)1-(2,4-Dichlorobenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 344 (M+1); Rt=4.41 min.

Example 821 General Procedure (L)1-(3-Methoxybenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 306 (M+1); Rt=3.64 min.

Example 822 General Procedure (L)1-(4-Fluorobenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 294 (M+1); Rt=3.71 min.

Example 823 General Procedure (L)1-(3-Fluorobenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 294 (M+1); Rt=3.68 min.

Example 824 General Procedure (L)1-(2-Iodobenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 402 (M+1); Rt=4.11 min.

Example 825 General Procedure (L)1-[(Naphthalen-2-yl)methyl]-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 326 (M+1); Rt=4.18 min.

Example 826 General Procedure (L)1-(3-Bromobenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 354 (M+1); Rt=4.08 min.

Example 827 General Procedure (L)1-(4-Carboxybenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

In this preparation, a larger excess of lithium bis(trimethylsilyl)amidein tetrahydrofuran (1.0 M, 1.7 mL, 1.7 mmol) was used.

HPLC-MS (Method B): m/z: 320 (M+1); Rt=2.84 min.

Example 828 General Procedure (L)1-(3-Carboxybenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

In this preparation, a larger excess of lithium bis(trimethylsilyl)amidein tetrahydrofuran (1.0 M, 1.7 mL, 1.7 mmol) was used.

HPLC-MS (Method B): m/z: 320 (M+1); Rt=2.91 min.

Example 829 General Procedure (L)1-(2,4-Difluorobenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 312 (M+1); Rt=3.78 min.

Example 830 General Procedure (L)1-(3,5-Difluorobenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 312 (M+1); Rt=3.78 min.

Example 831 General Procedure (L)1-(3,4-Difluorobenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 312 (M+1); Rt=3.81 min.

Example 832 General Procedure (L)1-[4-(2-Propyl)benzyl]-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 318 (M+1); Rt=4.61 min.

Example 833 General Procedure (L)1-(3,5-Dimethoxybenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 336 (M+1); Rt=3.68 min.

Example 834 General Procedure (L)

1-(2′-Cyanobiphenyl-4-yl methyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 377 (M+1); Rt=4.11 min.

Example 835 General Procedure (L)1-(2-Methylbenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 290 (M+1); Rt=3.98 min.

Further compounds of the invention that may be prepared according togeneral procedure (K) and/or (L) includes: Example 836

Example 837

Example 838

Example 839

Example 840

Example 841

Example 842

Example 843

Example 844

Example 845

Example 846

Example 847

Example 848

Example 849

Example 850

Example 851

Example 852

Example 853

Example 854

Example 855

Example 856

Example 857

Example 858

Example 859

The following compounds of the invention may be prepared eg. from1-(4-bromobenzyl)-5-(2H-tetrazol-5-yl)-1H-indole (example 807) or fromthe analogue 1-(3-bromobenzyl)-5-(2H-tetrazol-5-yl)-1H-indole and arylboronic acids via the Suzuki coupling reaction eg as described inLittke, Dai & Fu J. Am. Chem. Soc., 2000, 122, 4020-8 (or referencescited therein), or using the methodology described in general procedure(E), optionally changing the palladium catalyst tobis(tri-tert-butylphosphine)palladium (0). Example 860

Example 861

Example 862

Example 863

Example 864

General Procedure (M) for Preparation of Compounds of General FormulaI₁₂:

wherein T is as defined above.

The general procedure (M) is further illustrated by the followingexample:

Example 865 General Procedure (M)1-Benzoyl-5-(2H-tetrazol-5-yl)-1H-indole

To a solution of 5-cyanoindole (1.0 g, 7.0 mmol) in dichloromethane (8mL) was added 4-(dimethylamino)pyridine (0.171 g, 1.4 mmol),triethylamine (1.96 mL, 1.42 g, 14 mmol) and benzoyl chloride (0.89 mL,1.08 g, 7.7 mmol). The resulting mixture was stirred for 18 hours atroom temperature. The mixture was diluted with dichloromethane (80 mL)and washed consecutively with a saturated solution of sodiumhydrogencarbonate (40 mL) and brine (40 mL). The organic phase was driedwith magnesium sulfate (1 hour). Filtration and concentration furnishedthe crude material which was purified by flash chromatography on silicagel, eluting with ethyl acetate/heptanes=2:3.1-Benzoyl-1H-indole-5-carbonitrile was obtained as a solid.

HPLC-MS (Method C): m/z: 247 (M+1); Rt=4.07 min.

1-Benzoyl-1H-indole-5-carbonitrile was transformed into1-benzoyl-5-(2H-tetrazol-5-yl)-1H-indole by the method described inexample 594.

HPLC (Method C): Rt=1.68 min.

The compound in the following example was prepared by the sameprocedure.

Example 866 General Procedure (M)1-Benzoyl-4-(2H-tetrazol-5-yl)-1H-indole

1-Benzoyl-1H-indole-4-carbonitrile was prepared from 4-cyanoindoleaccording to the method described in example 865.

HPLC-MS (Method C): m/z: 247 (M+1); Rt=4.24 min.

1-Benzoyl-4-(2H-tetrazol-5-yl)-1H-indole was prepared from1-benzoyl-1H-indole-4-carbonitrile according to the method described inexample 594.

HPLC (Method C): Rt=1.56 min.

Example 867 General Procedure (M)(2-Fluoro-3-trifluoromethylphenyl)-[5-(2H-tetrazol-5-yl)-indol-1-yl]-methanone

HPLC-MS (Method B): m/z=376 (M+1); Rt=4.32 min.

Example 868 General Procedure (M)(4-Methoxyphenyl)-[5-(2H-tetrazol-5-yl)-indol-1-yl]-methanone

HPLC-MS (Method B): m/z=320 (M+1); Rt=3.70 min.

Example 869 General Procedure (M)(3-Nitrophenyl)-[5-(2H-tetrazol-5-yl)-indol-1-yl]-methanone

HPLC-MS (Method B): m/z=335 (M+1); Rt=3.72 min.

Example 870 General Procedure (M)(4-Nitrophenyl)-[5-(2H-tetrazol-5-yl)-indol-1-yl]-methanone

HPLC-MS (Method B): m/z=335 (M+1); Rt=3.71 min.

Example 871 General Procedure (M)Naphthalen-2-yl-[5-(2H-tetrazol-5-yl)-indol-1-yl]-methanone

HPLC-MS (Method C): m/z=340 (M+1); Rt=4.25 min.

Example 872 General Procedure (M)(2,3-Difluorophenyl)-[5-(2H-tetrazol-5-yl)-indol-1-yl]-methanone

HPLC-MS (Method B: m/z=326 (M+1); Rt=3.85 min.

The following known and commercially available compounds do all bind tothe His B10 Zn²⁺ site of the insulin hexamer:

Example 873 1-(4-Fluorophenyl)-5-(2H-tetrazol-5-yl)-1H-indole

Example 874 1-Amino-3-(2H-tetrazol-5-yl)benzene

Example 875 1-Amino-4-(2H-tetrazol-5-yl)benzene

A mixture of 4-aminobenzonitrile (10 g, 84.6 mmol), sodium azide (16.5g, 254 mmol) and ammonium chloride (13.6 g, 254 mmol) in DMF was heatedat 125° C. for 16 hours. The cooled mixture was filtered and thefiltrate was concentrated in vacuo. The residue was added water (200 mL)and diethyl ether (200 mL) which resulted in crystallisation. Themixture was filtered and the solid was dried in vacuo at 40° C. for 16hours to afford 5-4-aminophenyl)-2H-tetrazole.

¹H NMR DMSO-d₆): δ=5.7 (3H, bs), 6.69 (2H, d), 7.69 (2H, d). HPLC-MS(Method C): m/z: 162 (M+1); Rt=0.55 min.

Example 8761 Nitro-4-(2H-tetrazol-5-yl)benzene

Example 8771 Bromo-4-(2H-tetrazol-5-yl)benzene

General Procedure (N) for Solution Phase Preparation of Amides ofGeneral Formula I₁₃:

wherein Frag is any fragment carrying a carboxylic acid group, R ishydrogen, optionally substituted aryl or C₁₋₈-alkyl and R′ is hydrogenor C₁₋₄-alkyl.

Frag-CO₂H may be prepared eg by general procedure (D) or by othersimilar procedures described herein, or may be commercially available.

The procedure is further illustrated in the following example 878:

Example 878 General Procedure (N)N-(4-Chlorobenzyl)-2-[3-(2,4-dioxothiazolidin-5-ylidenemethyl)-1H-indol-1-yl]acetamide

[3-(2,4-Dioxothiazolidin-5-ylidenemethyl)indol-1-yl]acetic acid (example478, 90.7 mg, 0.3 mmol) was dissolved in NMP (1 mL) and added to amixture of 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide, hydrochloride(86.4 mg, 0.45 mmol) and 1-hydroxybenzotriazol (68.8 mg, 0.45 mmol) inNMP (1 mL). The resulting mixture was shaken at RT for 2 h.4-Chlorobenzylamine (51 mg, 0.36 mmol) and DIPEA (46.4 mg, 0.36 mmol) inNMP (1 mL) were added to the mixture and the resulting mixture shaken atRT for 2 days. Subsequently ethyl acetate (10 mL) was added and theresulting mixture washed with 2×10 mL water followed by saturatedammonium chloride (5 mL). The organic phase was evaporated to drynessgiving 75 mg (57%) of the title compound.

HPLC-MS (Method C): m/z: 426 (M+1); Rt.=3.79 min.

Example 879 General Procedure (N)N-(4-Chlorobenzyl)-4-[2-chloro-4-(2,4-dioxothiazolidin-5-ylidenemethyl)phenoxy]butyramide

HPLC-MS (Method A): m/z: 465 (M+1); Rt=4.35 min.

Example 880 General Procedure (N)N-(4-Chlorobenzyl)-4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)phenoxy]butyramide

HPLC-MS (Method A): m/z: 431 (M+1); Rt=3.68 min.

Example 881 General Procedure (N)2-[2-Bromo-4-(2,4-dioxothiazolidin-5-ylidenemethyl)phenoxy]-N-(4-chlorobenzyl)acetamide

HPLC-MS (Method A): m/z: 483 (M+1); Rt=4.06 min.

Example 882 General Procedure (N)N-(4-Chlorobenzyl)-2-[3-(2,4-dioxothiazolidin-5-ylidenemethyl)phenoxy]acetamide

HPLC-MS (Method A): m/z: 403 (M+1); Rt=4.03 min.

Example 883 General Procedure (N)N-(4-Chlorobenzyl)-3-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)phenyl]acrylamide

HPLC-MS (Method A): m/z: 399 (M+1); Rt=3.82.

Example 884 General Procedure (N)N-(4-Chlorobenzyl)-4-[3-(2,4-dioxothiazolidin-5-ylidenemethyl)phenoxy]butyramide

HPLC-MS (Method A): m/z: 431 (M+1); Rt=3.84 min.

Example 885 General Procedure (N)4-[2-Bromo-4-(2,4-dioxothiazolidin-5-ylidenemethyl)phenoxy]-N-(4-chlorobenzyl)butyramide

HPLC-MS (Method A): m/z: 511 (M+1); Rt=4.05 min.

Example 886 General Procedure (N)4-[2-Bromo-4-(4-oxo-2-thioxothiazolidin-5-ylidenemethyl)-phenoxy]-N-(4-chlorobenzyl)-butyramide

HPLC-MS (Method A): m/z: 527 (M+1); Rt=4.77 min.

Example 887 General Procedure (N)N-(4-Chlorobenzyl)-2-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)naphthalen-1-yloxy]acetamide

HPLC-MS (Method C): m/z: 431 (M+1); Rt.=4.03 min.

Example 888 General Procedure (N)N-(4-Chlorobenzyl)-3-[3-(2,4-dioxothiazolidin-5-ylidenemethyl)-1H-indol-1-yl]propionamide

HPLC-MS (Method C): m/z: 440 (M+1); Rt.=3.57 min.

Example 889 General Procedure (N)N-(4-Chlorobenzyl)-4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)naphthalen-1-yloxy]butyramide

HPLC-MS (Method C): m/z: 481 (M+1); Rt=4.08 min.

Example 890 General Procedure (N)4-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)-naphthalen-1-yloxy]-N-hexylbutyramide

HPLC-MS (Method C): m/z: 441 (M+1); Rt=4.31 min.

Example 891 General Procedure (N)4-({[3-(2,4-Dioxothiazolidin-5-ylidenemethyl)indole-7-carbonyl]amino}methyl)benzoicacid methyl ester

HPLC-MS (Method C): m/z: 436 (M+1); Rt.=3.55 min.

Example 892 General Procedure (N)N-(4-Chlorobenzyl)-4-[3-(2H-tetrazol-5-yl)carbazol-9-ylmethyl]benzamide

HPLC-MS (Method C): m/z:493 (M+1); Rt=4.19 min.

Example 893 General Procedure (N)N-(4-Chlorobenzyl)-3-[3-(2H-tetrazol-5-yl)carbazol-9-ylmethyl]benzamide

HPLC-MS (Method C): m/z: 493 (M+1); Rt=4.20 min.

Example 894 General Procedure (N)N-(4-Chlorobenzyl)-3-methyl-4-[3-(2H-tetrazol-5-yl)-carbazol-9-ylmethyl]benzamide

HPLC-MS (Method C): m/z: 507 (M+1); Rt=4.37 min.

Example 895 General Procedure (N)5-{2-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)-naphthalen-1-yloxy]-acetylamino}-isophthalicacid dimethyl ester

HPLC-MS (Method C): m/z=521 (M+1); Rt.=4.57 min.

Example 896 General Procedure (N)5-2-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)-naphthalen-1-yloxy]-acetylamino)isophthalicacid

HPLC-MS (Method C): m/z=515 (M+23); Rt.=3.09 min.

Example 897 General Procedure (N)5-(3-2-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)-naphthalen-1-yloxy]-ethyl}-ureido)-isophthalicacid monomethyl ester

HPLC-MS (Method C): m/z=536 (M+1); Rt=3.58 min.

Example 898 General Procedure (N)2-{4-[3-(2H-Tetrazol-5-yl)carbazol-9-ylmethyl]benzoylamino}succinic aciddimethyl ester

4-[3-(1H-Tetrazol-5-yl)carbazol-9-ylmethyl]benzoic acid (2.00 g, 5.41mmol), 1-hydroxybenzotriazole (1.46 g, 10.8 mmol) andN,N-di(2-propyl)ethylamine (4.72 mL, 3.50 g, 27.1 mmol) were dissolvedin dry N,N-dimethylformamide (60 mL). The mixture was cooled in anice-water bath, and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (1.45 g, 7.56 mmol) and (S)-aminosuccinic acid dimethylester hydrochloride (1.28 g, 6.48 mmol) were added. The cooling wasdiscontinued, and the reaction mixture was stirred at room temperaturefor 18 hours before it was poured into hydrochloric acid (0.1 N, 600mL). The solid was collected by filtration and washed with water (2×25mL) to furnish the title compound.

HPLC-MS (Method C): m/z: 513 (M+1); Rt=3.65 min. ¹H-NMR (DMSO-d₆): δ8.90 (1H, d), 8.86 (1H, d), 8.29 (1H, d), 8.11 (1H, dd), 7.87 (1H, d),7.75 (2H, d), 7.69 (1H, d), 7.51 (1H, t), 7.32 (1H, t), 7.28 (2H, d),5.82 (2H, s), 4.79 (1H, m), 3.61 (3H, s), 3.58 (3H, s), 2.92 (1H, dd),2.78 (1H, dd).

Example 899 General Procedure (N)2-{4-[3-(2H-Tetrazol-5-yl)carbazol-9-ylmethyl]benzoylamino}succinic acid

2-{4-[3-(2H-Tetrazol-5-yl)carbazol-9-ylmethyl]benzoylamino}succinic aciddimethyl ester (1.20 g, 2.34 mmol) was dissolved in tetrahydrofuran (30mL). Aqueous sodium hydroxide (1 N, 14 mL) was added, and the resultingmixture was stirred at room temperature for 18 hours. The reactionmixture was poured into hydrochloric acid (0.1 N, 500 mL). The solid wascollected by filtration and washed with water (2×25 mL) and diethylether (2×25 mL) to furnish the title compound.

HPLC-MS (Method C): m/z: 485 (M+1); Rt=2.94 min. ¹H-NMR (DMSO-d₆): δ12.44 (2H, s (br)), 8.90 (1H, d), 8.68 (1H, d), 8.29 (1H, d), 8.11 (1H,dd), 7.87 (1H, d), 7.75 (2H, d), 7.68 (1H, d), 7.52 (1H, t), 7.32 (1H,t), 7.27 (2H, d), 5.82 (2H, s), 4.70 (1H, m), 2.81 (1H, dd), 2.65 (1H,dd).

The compounds in the following examples were prepared in a similarfashion.

Example 900 General Procedure (N)2-{4-[3-(2H-Tetrazol-5-yl)-carbazol-9-ylmethyl]-benzoylamino}-succinicacid dimethyl ester

HPLC-MS (Method C): m/z=513 (M+l); Rt=3.65 min.

Example 901 General Procedure (N)2-{4-[3-(2H-Tetrazol-5-yl)carbazol-9-ylmethyl]benzoylamino}pentanedioicacid dimethyl ester

HPLC-MS (Method C): m/z=527 (M+1); Rt=3.57 min.

Example 902 General Procedure (N)(Methoxycarbonylmethyl-{4-[3-(2H-tetrazol-5-yl)-carbazol-9-ylmethyl]-benzoyl}-amino)-aceticacid methyl ester

HPLC-MS (Method C): m/z=513 (M+1); Rt=3.55 min.

Example 903 General Procedure (N)2-{4-[3-(2H-Tetrazol-5-yl)carbazol-9-ylmethyl]benzoylamino}pentanedioicacid

HPLC-MS (Method C): m/z=499 (M+1); Rt=2.87 min.

Example 904 General Procedure (N)(Ethoxycarbonylmethyl-{4-[3-(2H-tetrazol-5-yl)-carbazol-9-ylmethyl]-benzoyl}-amino)-aceticacid ethyl ester

HPLC-MS (Method C): m/z=541 (M+1); Rt=3.91 min.

Example 905 General Procedure (N)3-(3-{4-[4-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-naphthalen-1-yloxy]-butyrylamino}-propylamino)-hexanedioicacid dimethyl ester

HPLC-MS (Method C: m/z=585 (M+1); Rt=2.81 min.

Example 906 General Procedure (N)3-(3-{4-[4-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-naphthalen-1-yloxy]-butyrylamino}-propylamino)-hexanedioicacid

HPLC-MS (Method C): m/z=554 (M−3); Rt=3.19 min.

Example 907 General Procedure (N)(Carboxymethyl-{4-[3-2H-tetrazol-5-yl)-carbazol-9-ylmethyl]-benzoyl}-amino)-aceticacid

HPLC-MS (Method C): m/z=485 (M+1); Rt=3.04 min.

Example 908 General Procedure (N)4-(3-{4-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)-naphthalen-1-yloxy]-butyrylamino}-propylamino)-cyclohexane-1,3-dicarboxylicacid dimethyl ester

HPLC-MS (Method C): m/z=612 (M+1); Rt=3.24 min.

Example 909 General Procedure (N)2-{3-[3-(2H-Tetrazol-5-yl)carbazol-9-ylmethyl]benzoylamino}pentanedioicacid dimethyl ester

HPLC-MS (Method C): m/z=527 (M+1); Rt=3.65 min.

Example 910 General Procedure (N)2-{3-[3-(2H-Tetrazol-5-yl)carbazol-9-ylmethyl]benzoylamino}pentanedioicacid dimethyl ester

HPLC-MS (Method C): m/z=527 (M+1); Rt=3.65 min.

Example 911 General Procedure (N)2-{3-[3-(2H-Tetrazol-5-yl)carbazol-9-ylmethyl]benzoylamino}pentanedioicacid dimethyl ester

HPLC-MS (Method C): m/z=527 (M+1); Rt=3.65 min.

Example 912 General Procedure (N)2-{3-[3-(2H-Tetrazol-5-yl)carbazol-9-ylmethyl]benzoylamino}pentanedioicacid

HPLC-MS (Method C): m/z=499 (M+1); Rt=3.00 min.

Example 913 General Procedure (N)(Methoxycarbonylmethyl-{3-[3-(2H-tetrazol-5-yl)carbazol-9-ylmethyl]benzoyl}amino)aceticacid methyl ester

¹H-NMR (DMSO-d₆): δ 8.88 (1H, d), 8.29 (1H, d), 8.10 (1H, dd), 7.85 (1H,d), 7.67 (1H, d), 7.52 (1H, t), 7.39 (1H, t), 7.30 (2H, m), 7.17 (2H,m), 5.79 (2H, s), 4.17 (2H, s), 4.02 (2H, s), 3.62 (3H, s), 3.49 (3H,s).

Example 914 General Procedure (N)2-{3-[3-(2H-Tetrazol-5-yl)carbazol-9-ylmethyl]benzoylamino}succinic aciddimethyl ester

HPLC-MS (Method C): m/z=513 (M+1); Rt=3.70 min.

Example 915 General Procedure (N)2-{3-[3-(2H-Tetrazol-5-yl)-carbazol-9-ylmethyl]-benzoylamino}-succinicacid

HPLC-MS (Method C): m/z=485 (M+1); Rt=2.96 min.

Example 916 General Procedure (N)(Carboxymethyl-{3-[3-(2H-tetrazol-5-yl)carbazol-9-ylmethyl]benzoyl}amino)aceticacid

HPLC-MS (Method C): m/z=485 (M+1); Rt=2.87 min.

Example 917 General Procedure (N)4-(4-(3-Carboxy-propylcarbamoyl)4-{4-[3-(2H-tetrazol-5-yl)carbazol-9-ylmethyl]-benzoylamino}-butyrylamino)-butyricacid

The title compound was prepared by coupling of(S)-2-{4-[3-(2H-tetrazol-5-yl)carbazol-9-ylmethyl]benzoylamino)pentanedioicacid bis-(2,5-dioxopyrrolidin-1-yl) ester (prepared from(S)-2-{4-[3-(2H-tetrazol-5-yl)carbazol-9-ylmethyl]benzoylamino}pentanedioicacid by essentially the same procedure as described for the synthesis of4-[3-(2H-tetrazol-5-yl)carbazol-9-ylmethyl]benzoic acid2,5-dioxopyrrolidin-1-yl ester) with 4-aminobutyric acid according tothe procedure described for the preparation of4-{4-[3-(2H-tetrazol-5-yl)carbazol-9-ylmethyl]benzoylamino}butyric acid.

HPLC-MS (Method C): m/z: 669 (M+1); Rt=2.84 min.

Example 918 General Procedure (N)[2-(2-{4-[3-(2H-Tetrazol-5-yl)-carbazol-9-ylmethyl]benzoylamino}ethoxy)ethoxy]aceticacid

HPLC-MS (Method C): m/z: 515 (M+1); Rt=3.10 min.

Example 919 General Procedure (N)2-{4-[3-(2H-Tetrazol-5-yl)-carbazol-9-ylmethyl]-benzoylamino-pentanedioicacid di-tert-butyl ester

HPLC-MS (Method C): m/z=611 (M+1); Rt=4.64 min.

Example 920 General Procedure (N)4-{4-[3-(2H-Tetrazol-5-yl)carbazol-9-ylmethyl]benzoylamino}butyric Acid

HPLC-MS (Method C): m/z: 455 (M+1); Rt=3.13 min.

Example 921 General Procedure (N)[2-(2-{4-[3-(2H-Tetrazol-5-yl)carbazol-9-ylmethyl]benzoylamino}ethoxy)ethoxy]aceticacid

The title compound was prepared by coupling of4-[3-(2H-tetrazol-5-yl)carbazol-9-ylmethyl]benzoic acid2,5-dioxopyrrolidin-1-yl ester with [2-(2-aminoethoxy)ethoxy]acetic acid(prepared from [2-[2-(Fmoc-amino)ethoxy]ethoxy]acetic acid by treatmentwith PS-Trisamine resin in DMF).

HPLC-MS (Method C): m/z: 515 (M+1); Rt=3.10 min.

The commercially available compounds in the following examples do allbind to the HisB10 Zn²⁺ site:

Example 922 1-(4-Bromo-3-methylphenyl)-1,4-dihydrotetrazole-5-thione

Example 923 1-(4-Iodophenyl)-1,4-dihydrotetrazole-5-thione

Example 924 1-(2,4,5-Trichlorophenyl)-1H-tetrazole-5-thiol

Example 925 1-(2,6-Dimethylphenyl)-1,4-dihydrotetrazole-5-thione

Example 926 1-(2,4,6-Trimethylphenyl)-1,4-dihydrotetrazole-5-thione

Example 927 1-(4-Dimethylaminophenyl)-1H-tetrazole-5-thiol

Example 928 1-(3,4-Dichlorophenyl)-1,4-dihydro-1H-tetrazole-5-thione

Example 929 1-(4-Propylphenyl)-1,4-dihydro-1H-tetrazole-5-thione

Example 930 1-(3-Chlorophenyl)-1,4-dihydro-1H-tetrazole-5-thione

Example 931 1-(2-Fluorophenyl)-1,4-dihydro-1H-tetrazole-5-thione

Example 932 1-(2,4-Dichlorophenyl)-1,4-dihydro-1H-tetrazole-5-thione

Example 9331-(4-Trifluoromethoxyphenyl)-1,4-dihydro-1H-tetrazole-5-thione

Example 934 N-[4-(5-Mercaptotetrazol-1-yl)-phenyl]-acetamide

Example 935 1-(4-Chlorophenyl)-1,4-dihydrotetrazole-5-thione

Example 936 1-(4-Methoxyphenyl)-1,4-dihydrotetrazole-5-thione

Example 9371-(3-Fluoro-4-pyrrolidin-1-ylphenyl)-1,4-dihydrotetrazole-5-thione

Example 938 N-[3-(5-Mercaptotetrazol-1-yl)phenyl]acetamide

Example 939 1-(4-Hydroxyphenyl)-5-mercaptotetrazole

Example 940

Preparation of 1-aryl-1,4-dihydrotetrazole-5-thiones (or the tautomeric1-aryltetrazole-5-thiols) is described in the literature (eg. by Kauer &Sheppard, J. Org. Chem., 32, 3580-92 (1967)) and is generally performedeg. by reaction of aryl-isothiocyanates with sodium azide followed byacidification

1-Aryl-1,4-dihydrotetrazole-5-thiones with a carboxylic acid tethered tothe aryl group may be prepared as shown in the following scheme:

Step 1 is a phenol alkylation and is very similar to steps 1 and 2 ofgeneral procedure (D) and may also be prepared similarly as described inexample 481.

Step 2 is a reduction of the nitro group. SnCl₂, H₂ over Pd/C and manyother procedures known to those skilled in the art may be utilised.

Step 3 is formation of an arylisothiocyanate from the correspondinganiline. As reagents CS₂, CSCl₂, or other reagents known to thoseskilled in the art, may be utilised.

Step 4 is a conversion to mercaptotetrazole as described above.Compounds of the invention include: Example 941

Example 942

Example 943

Example 944

Example 945

Example 946

Example 947

Example 948 4-(4-Hydroxyphenyl)-1H-[1,2,3]triazole-5-carbonitrile

Phenylsulphonyl acetonitrile (2.0 g, 11.04 mmol) was mixed with4-hydroxybenzaldehyde (1.35 g, 11.04 mmol) in DMF (10 mL) and toluene(20 mL). The mixture was refluxed for 3 hours and subsequentlyevaporated to dryness in vacuo. The residue was treated with diethylether and toluene. The solid formed was filtered to afford 2.08 g (66%)of 2-benzenesulfonyl-3-(4-hydroxyphenyl)acrylonitrile.

HPLC-MS (Method C): m/z: 286 (M+1); Rt.=3.56 min.

A mixture of 2-benzenesulfonyl-3-(4-hydroxyphenyl)acrylonitrile (2.08 g,7.3 mmol) and sodium azide (0.47 g, 7.3 mmol) in DMF (50 mL) was heatedat reflux temperature 2 hours. After cooling, the mixture was poured onice. The mixture was evaporated in vacuo to almost dryness and toluenewas added. After filtration, the organic phase was evaporated in vacuo.The residue was purified by silicagel chromatography eluting with amixture of ethyl acetate and heptane (1:2). This afforded 1.2 g (76%) ofthe title compound.

1H NMR (DMSO-d₆): 10.2 (broad,1H); 7.74 (d,2H); 6.99 (d,2H); 3.6-3.2(broad,1H). HPLC-MS (Method C) m/z:=187 (M+1); Rt.=1.93 min

General Procedure (O) for Preparation of Compounds of General FormulaI₁₄:

wherein

-   -   AA is as defined above,

Steps 1 and 2 are described in the literature (eg Beck & Gûnther, Chem.Ber., 106, 2758-66 (1973))

Step 1 is a Knoevenagel condensation of the aldehyde AA-CHO withphenylsulfonyl-acetonitrile and step 2 is a reaction of thevinylsulfonyl compound obtained in step 1 with sodium azide. Thisreaction is usually performed in DMF at 90-110° C.

This general procedure is further illustrated in the following example949:

Example 949 General Procedure (O)[4-(5-Cyano-1H-[1,2,3]triazol-4-yl)phenoxy]acetic acid

Phenylsulphonylacetonitrile (0.1 g, 0.55 mmol) was mixed with4-formylphenoxyactic acid (0.099 g, 0.55 mmol) in DMF (3 mL) and heatedto 110° C. for 3 h and subsequently cooled to RT. Sodium azide (0.036 g,0.55 mmol) was added and the resulting mixture was heated to 110° C. for3 h and cooled to RT. The mixture was poured into water (20 mL) andcentrifuged. The supernatant was discarded, ethanol (5 mL) was added andthe mixture was centrifuged again. After discarding the supernatant, theresidue was dried in vacuo to afford 50 mg (37%) of[4-(5-Cyano-1H-[1,2,3]triazol-4-yl)phenoxy]acetic acid.

HPLC-MS (Method C): m/z: 245 (M+1) Rt. 2.19 min.

Example 950 General Procedure (O)5-(Naphthalen-1-yl)-3H-[1,2,3]triazole-4-carbonitrile

HPLC-MS (Method C): m/z: 221 (M+1); Rt. 3.43 min.

Example 951 General Procedure (O)5-(Naphthalen-2-yl)-3H-[1,2,3]triazole-4-carbonitrile

HPLC-MS (Method C): m/z: 221 (M+1); Rt=3.66 min.

Example 952 General Procedure (O)4-[3-(5-Cyano-[1,2,3]triazol-4-yl)-1,4-dimethylcarbazol-9-ylmethyl]-benzoicacid

HPLC-MS (Method C): m/z=422 (M+1); Rt=3.85 min.

Preparation of Intermediary Aldehyde:

1,4 Dimethylcarbazol-3-carbaldehyde (0.68 g, 3.08 mmol) was dissolved indry DMF (15 mL), NaH (diethyl ether washed) (0.162 g, 6.7 mol) wasslowly added under nitrogen and the mixture was stirred for 1 hour atroom temperature. 4-Bromomethylbenzoic acid (0.73 g, 3.4 mmol) wasslowly added and the resulting slurry was heated to 40° C. for 16 hours.Water (5 mL) and hydrochloric acid (6N, 3 mL) were added. After stirringfor 20 min at room temperature, the precipitate was filtered off andwashed twice with acetone to afford after drying 0.38 g (34%) of4-(3-formyl-1,4-dimethylcarbazol-9-ylmethyl)benzoic acid.

HPLC-MS (Method C): m/z=358 (M+1), RT.=4.15 min.

Example 953 General Procedure (O)5-(Anthracen-9-yl)-3H-[1,2,3]triazole-4-carbonitrile

HPLC-MS (Method C): m/z: 271 (M+1); Rt=3.87 min.

Example 954 General Procedure (O)5-(4-Methoxynaphthalen-1-yl)-3H-[1,2,3]triazole-4-carbonitrile

HPLC-MS (Method C): m/z: 251 (M+1); Rt=3.57 min.

Example 955 General Procedure (O)5-(1,4-Dimethyl-9H-carbazol-3-yl)-3H-[1,2,3]triazole-4-carbonitrile

HPLC-MS (Method C): m/z: 288 (M+1); Rt=3.67 min.

Example 956 General Procedure (O)5-(4′-Methoxybiphenyl-4-yl)-3H-[1,2,3]triazole-4-carbonitrile

HPLC-MS (Method C): m/z=277 (M+1); Rt=3.60 min.

Example 957 General Procedure (O)5-(4-Styrylphenyl)-3H-[1,2,3]triazole-4-carbonitrile

HPLC-MS (Method C): m/z=273 (M+1); Rt=4.12 min.

Example 958 General Procedure (O)5-(2,6-Dichloro-4-dibenzylaminophenyl)-3H-[1,2,3]triazole-4-carbonitrile

HPLC-MS (Method C): m/z=434 (M+1); Rt=4.64 min.

Example 959 General Procedure (O)5-(1-Bromonaphthalen-2-yl)-3H-[1,2,3]triazole-4-carbonitrile

HPLC-MS (Method C: m/z=300 (M+1); Rt.=3.79 min.

Example 960 4-(4-Bromophenyl)-1H-[1,2,3]triazole-5-carbonitrile

This compound is commercially available (MENAI).

Example 961 N-[4-(5-Cyano-1H-[1,2,3]triazol-4-yl)-phenyl]-acetamide

This compound is commercially available (MENAI).

Example 962 General Procedure (O)5-(4′-Chlorobiphenyl-4-yl)-3H-[1,2,3]triazole4-carbonitrile

HPLC-MS (Method C): m/z=281 (M+1); Rt=4.22 min.

The compounds in the following examples are commercially available andmay be prepared using a similar methodology:

Example 9634-(4-Trifluoromethoxyphenyl)-1H-[1,2,3]triazole-5-carbonitrile

Example 964 4-Benzo[1,3]dioxol-5-yl-1H-[1,2,3]triazole-5-carbonitrile

Example 9654-(3-Trifluoromethylphenyl)-1H-[1,2,3]triazole-5-carbonitrile

Example 966 4-Pyridin-3-yl-1H-[1,2,3]triazole-5-carbonitrile

Example 967 4-(2,6-Dichlorophenyl)-1H-[1,2,3]triazole-5-carbonitrile

Example 968 4-Thiophen-2-yl-1H-[1,2,3]triazole-5-carbonitrile

Example 969 3,5-Dimethylisoxazole-4-carboxylic acid4-(5-cyano-1H-[1,2,3]triazol-4-yl)phenyl ester

Example 970 3,3-Dimethyl-butyric acid4-(5-cyano-1H-[1,2,3]triazol-4-yl)phenyl ester

Example 971 4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid4-(5-cyano-1H-[1,2,3]triazol-4-yl)phenyl ester

Example 972 4-Chlorobenzoic acid4-(5-cyano-1H-[1,2,3]triazol-4-yl)phenyl ester

Example 973 4-(3-Phenoxyphenyl)-1H-[1,2,3]triazole-5-carbonitrile

Example 9744-(5-Bromo-2-methoxyphenyl)-1H-[1,2,3]triazole-5-carbonitrile

Example 9754-(2-Chloro-6-fluorophenyl)-1H-[1,2,3]triazole-5-carbonitrile

The following cyanotriazoles are also compounds of the invention:

-   4-(2-Chloro-6-fluorophenyl)-1H-[1,2,3]triazole-5-carbonitrile.-   Terephthalic acid    mono[4-(5-cyano-1H-[1,2,3]triazol-4-yl)phenyl]ester.-   N-[4-(5-cyano-1H-[1,2,3]triazol-4-yl)-phenyl]terephthalamic acid-   4-(4-Octyloxyphenyl)-1H-[1,2,3]triazole-5-carbonitrile-   4-(4-Styrylphenyl)-1H-[1,2,3]triazole-5-carbonitrile.-   4-(4′-Trifluoromethylbiphenyl-4-yl)-1H-[1,2,3]triazole-5-carbonitrile.-   4-(4′-Chlorobiphenyl-4-yl)-1H-[1,2,3]triazole-5-carbonitrile.-   4-(4′-Methoxybiphenyl-4-yl)-1H-[1,2,3]triazole-5-carbonitrile.-   4-(1-Naphthyl)-1H-[1,2,3]triazole-5-carbonitrile.-   4-(9-Anthranyl)-1H-[1,2,3]triazole-5-carbonitrile.-   4-(4-Methoxy-1-naphthyl)-1H-[1,2,3]triazole-5-carbonitrile.-   4-(4-Aminophenyl)-1H-[1,2,3]triazole-5-carbonitrile.-   4-(2-Naphthyl)-1H-[1,2,3]triazole-5-carbonitrile.

General Procedure (P) for Preparation of Compounds of General FormulaI₁₅:

wherein

-   -   n is 1 or 3-20,    -   AA is as defined above,    -   R″ is a standard carboxylic acid protecting group, such as        C₁-C₆-alkyl or benzyl and Lea is a leaving group, such as        chloro, bromo, iodo, methanesulfonyloxy, toluenesulfonyloxy or        the like.

This procedure is very similar to general procedure (D), steps 1 and 2are identical.

Steps 3 and 4 are described in the literature (eg Beck & Gûnther, iChem. Ber., 106, 2758-66 (1973))

Step 3 is a Knoevenagel condensation of the aldehyde obtained in step 2with phenylsulfonylacetonitrile and step 4 is a reaction of thevinylsulfonyl compound obtained in step 3 with sodium azide. Thisreaction is usually performed in DMF at 90-110° C.

This General procedure (P) is further illustrated in the following twoexamples

Example 976 General Procedure (P)5-[6-(5-Cyano-1H-[1,2,3]triazol-4-yl)-naphthalen-2-yloxy]-pentanoic acidethyl ester

6-Hydroxynaphthalene-2-carbaldehyde (Syncom BV. NL, 15.5 g, 90 mmol) andK₂CO₃ (62.2 g, 450 mmol) were mixed in DMF (300 mL) and stirred at roomtemperature for 1 hour. Ethyl 5-bromovalerate (21.65 g, 103.5 mmol) wasadded and the mixture was stirred at room temperature for 16 hours.Activated carbon was added and the mixture was filtered. The filtratewas evaporated to dryness in vacuo to afford 28.4 g of crude5-(6-formylnaphthalen-2-yloxy)pentanoic acid ethyl ester, which was usedwithout further purification.

HPLC-MS (Method C): m/z=301 (M+1); Rt.=4.39 min.

5-(6-Formylnaphthalen-2-yloxy)pentanoic acid ethyl ester (28.4 g, 94.5mmol), phenylsulfonylacetonitrile (20.6 g, 113.5 mmol), and piperidine(0.94 mL) were dissolved in DMF (200 mL) and the mixture was heated at50° C. for 16 hours. The resulting mixture was evaporated to dryness invacuo and the residue was dried for 16 hours at 40° C. in vacuo. Thesolid was recrystallised from 2-propanol (800 mL) and dried again asdescribed above. This afforded 35 g (80%) of5-[6-(2-benzenesulfonyl-2-cyanovinyl)naphthalen-2-yloxy]pentanoic acidethyl ester.

HPLC-MS (Method C): m/z=486 (M+23); Rt.=5.09 min.

5-[6-(2-Benzenesulfonyl-2-cyanovinyl)naphthalen-2-yloxy]pentanoic acidethyl ester (35 g, 74.6 mmol) and sodium azide (4.9 g, 75.6 mmol) weredissolved in DMF (100 mL) and stirred for 16 hours at 50° C. The mixturewas evaporated to dryness in vacuo, redissolved in THF/ethanol and asmall amount of precipitate was filtered off. The resulting filtrate waspoured into water (2.5 L). Filtration afforded after drying 24.5 g (88%)of 5-[6-(5-cyano-1H-[1,2,3]triazol-4-yl)naphthalen-2-yloxy]pentanoicacid ethyl ester (24.5 g, 88%).

HPLC-MS (Method C): m/z=365 (M+1); Rt.=4.36 min.

Example 977 General Procedure (B)5-[6-(5-Cyano-1H-[1,2,3]triazol-4-yl)-naphthalen-2-yloxy]-pentanoic acid

5-[6-(5-Cyano-1H-[1,2,3]triazol-4-yl)naphthalen-2-yloxy]pentanoicacidethyl ester (24.5 g, 67.4 mmol) was dissolved in THF (150 mL) and mixedwith sodium hydroxide (8.1 g, 202 mmol) dissolved in water (50 mL). Themixture was stirred for 2 days and the volatiles were evaporated invacuo. The resulting aqueous solution was poured into a mixture of water(1 L) and hydrochloric acid (1 N, 250 mL). The solid was isolated byfiltration, dissolved in sodium hydroxide (1 N, 200 mL), and thesolution was washed with DCM and then ethyl acetate, the aquous layerwas acidified with hydrochloric acid (12N). The precipitate was isolatedby filtration, dissolved in THF/diethyl ether, the solution was treatedwith MgSO₄ and activated carbon, filtrated and evaporated in vacuo toalmost dryness followed by precipitation by addition of pentane (1 L).This afforded after drying in vacuo 17.2 g (76%) of the title compound.

HPLC-MS (Method C): m/z=337 (M+1); Rt.=3.49 min.

Example 978 General Procedure (P)6-[6-(5-Cyano-1H-[1,2,3]triazol-4-yl)naphthalen-2-yloxy]hexanoic acid

HPLC-MS (Method C): m/z=351 (M+1); Rt=3.68 min.

Example 979 General Procedure (P)11-[6-(5-Cyano-1H-[1,2,3]triazol-4-yl)-naphthalen-2-yloxy]-undecanoicacid

HPLC-MS (Method C): m/z=443 (M+23); Rt=4.92 min.

Example 980 General Procedure (P)2-{3-[6-(5-Cyano-1H-[1,2,3]triazol-4-yl)-naphthalen-2-yloxy]-propyl}-malonicacid

HPLC-MS (Method C): m/z=465 (M+1); Rt.=4.95 min.

Example 981 General Procedure (P)2-{5-[6-(5-Cyano-1H-[1,2,3]triazol-4-yl)-naphthalen-2-yloxy]-pentyl}-malonicacid diethyl ester

HPLC-MS (Method C): m/z=465 (M+1); Rt.=4.95 min.

Example 982 General Procedure (P)2-{3-[6-(5-Cyano-1H-[1,2,3]triazol-4-yl)-naphthalen-2-yloxy]-propyl}-malonicacid

HPLC-MS (Method C): m/z=381 (M+1); Rt.=3.12 min.

Example 983 General Procedure (P)2-{5-[6-(5-Cyano-1H-[1,2,3]triazol-4-yl)-naphthalen-2-yloxy]-pentyl}-malonicacid

HPLC-MS (Method C): m/z 0 409 (M+1); Rt.=3.51 min.

Example 984 General Procedure (P)4-[4-(5-Cyano-1H-[1,2,3]triazol-4-yl)-phenoxy]butyric acid

HPLC-MS (Method C): m/z=273 (M+1); Rt=2.44 min.

The following compounds may be prepared according to this generalprocedure (P):

-   4-(4-(5-Cyano-1H-[1,2,3]triazol-4-yl)phenoxy)butyric acid:-   2-(4-(5-Cyano-1H-[1,2,3]triazol-4-yl)phenoxy)acetic acid:-   4-(4-(5-Cyano-1H-[1,2,3]triazol-4-yl)phenoxy)butyric acid ethyl    ester-   5-(4-(5-Cyano-1H-[1,2,3]triazol-4-yl)phenoxy)pentanoic acid-   8-(4-(5-Cyano-1H-[1,2,3]triazol-4-yl)phenoxy)octanoic acid-   10-(4-(5-Cyano-1H-[1,2,3]triazol-4-yl)phenoxy)decanoic acid-   12-(4-(5-Cyano-1H-[1,2,3]triazol-4-yl)phenoxy)dodecanoic acid

General Procedure (R) for Preparation of Compounds of General FormulaI₁₂:

wherein T is as defined above and R² and R³ are hydrogen, aryl or loweralkyl, both optionally substituted.

The general procedure (R) is further illustrated by the followingexample:

Example 985 General Procedure (R)Phenyl-[3-(2H-tetrazol-5-yl)-carbazol-9-yl]-methanone

2-Chlorotritylchloride resin (100 mg, 0.114 mmol active chloride) wasswelled in dichloromethane (4 mL) for 30 minutes. The solvent wasdrained, and a solution of 3-(2H-tetrazol-5-yl)-9H-carbazole (80 mg,0.34 mmol) in a mixture ofN,N-dimethylformamide/dichloromethane/N,N-di(2-propyl)ethylamine (5:5:1)(3 mL) was added. The reaction mixture was shaken at room temperaturefor 20 hours. The solvent was removed by filtration, and the resin waswashed thoroughly with N,N-dimethylformamide (2×4 mL) anddichloromethane (6×4 mL). A solution of 4-(dimethylamino)pyridine (14mg, 0.11 mmol) and N,N-di(2-propyl)ethylamine (0.23 mL, 171 mg, 1.32mmol) in N,N-dimethylformamide (2 mL) was added followed by benzoylchloride (0.13 mL, 157 mg, 1.12 mmol). The mixture was shaken for 48hours at room temperature. The drained resin was washed consecutivelywith dichloromethane (2×4 mL), methanol (2×4 mL) and tetrahydrofuran (4mL). The resin was treated for 2 hours at room temperature with asolution of dry hydrogen chloride in tetrahydrofuran/ethylether/ethanol=8:1:1 (0.1 M, 3 mL). The reaction mixture was drained andconcentrated. The crude product was stripped with dichloromethane (1.5mL) three times to yield the title compound.

HPLC-MS (Method C): m/z: 340 (M+1); Rt=3.68 min. ¹H-NMR (DMSO-d₆): δ8.91 (1H, s), 8.34 (1H, d), 8.05 (1H, d), 7.78 (3H, m), 7.63 (3H, m),7.46 (2H, m), 7.33 (1H, dd).

The compounds in the following examples were prepared in a similarfashion.

Example 986 General Procedure (R)Phenyl-[5-(2H-tetrazol-5-yl)-indol-1-yl]-methanone

HPLC-MS (Method C): m/z: 290 (M+1); Rt=3.04 min. ¹H-NMR (DMSO-d₆): δ8.46 (1H, d), 8.42 (1H, d), 8.08 (1H, dd), 7.82 (2H, d), 7.74 (1H, t),7.64 (2H, t), 7.55 (1H, d), 6.93 (1H, d).

Example 987 General Procedure (R)(2,3-Difluorophenyl)-[5-(2H-tetrazol-5-yl)-indol-1-yl]-methanone

HPLC-MS (Method B): m/z=326 (M+1); Rt=3.85 min.

Example 988 General Procedure (R)(2-Fluoro-3-trifluoromethylphenyl)-[5-(2H-tetrazol-5-yl)-indol-1-yl]-methanone

HPLC-MS (Method B): m/z=376 (M+1); Rt=4.32 min.

Example 989 General Procedure (R)(3-Nitrophenyl)-[5-(2H-tetrazol-5-yl)-indol-1-yl]-methanone

HPLC-MS (Method B): m/z=335 (M+1); Rt=3.72 min.

Example 990 General Procedure (R)(4-Nitrophenyl)-[5-(2H-tetrazol-5-yl)-indol-1-yl]-methanone

HPLC-MS (Method B): m/z=335 (M+1); Rt=3.71 min.

Example 991 General Procedure (R)Naphthalen-2-yl-[5-(2H-tetrazol-5-yl)-indol-1-yl]-methanone

HPLC-MS (Method C): m/z=340 (M+1); Rt=4.25 min.

Example 992 General Procedure (R)

HPLC-MS (Method C): m/z: 354 (M+1); Rt=3.91 min.

Example 993 General Procedure (R)

HPLC-MS (Method C): m/z: 418 (M+1); Rt=4.39 min.

Example 994 General Procedure (R)

HPLC-MS (Method C): m/z: 370 (M+1); Rt=4.01 min.

Example 995 General Procedure (R)

HPLC-MS (Method C): m/z: 374 (M+1); Rt=4.28 min.

Example 996 General Procedure (R)

HPLC-MS (Method C): m/z: 416 (M+1); Rt=4.55 min.

Example 997 General Procedure (R)

HPLC-MS (Method C): m/z: 354 (M+1); Rt=4.22 min.

Example 998 General Procedure (R)

HPLC-MS (Method C): m/z: 358 (M+1); Rt=3.91 min.

Example 999 General Procedure (R)

HPLC-MS (Method C): m/z: 390 (M+1); Rt=4.38 min.

Example 1000 General Procedure (R)

HPLC-MS (Method C): m/z: 418 (M+1); Rt=4.36 min.

Example 1001 General Procedure (R)

HPLC-MS (Method C): m/z: 304 (M+1); Rt=3.32 min.

Example 1002 General Procedure (R)

HPLC-MS (Method C): m/z: 368 (M+1); Rt=3.84 min.

Example 1003 General Procedure (R)

HPLC-MS (Method C): m/z: 320 (M+1); Rt=3.44 min.

Example 1004 General Procedure (R)

HPLC-MS (Method C): m/z: 324 (M+1); Rt=3.73 min.

Example 1005 General Procedure (R)

HPLC-MS (Method C): m/z: 304 (M+1); Rt=3.64 min.

Example 1006 General Procedure (R)

HPLC-MS (Method A): m/z: 308 (M+1); Rt=3.61 min.

Example 1007 General Procedure (R)

HPLC-MS (Method C): m/z: 368 (M+1); Rt=3.77 min.

Example 1008 General Procedure (R)

HPLC-MS (Method A): (sciex) m/z: 326 (M+1); Rt=3.73 min. HPLC-MS (MethodC): m/z: 326 (M+1); Rt=3.37 min.

Example 1009 General Procedure (R)

HPLC-MS (Method C): m/z: 374 (M+1); Rt=4.03 min.

Example 1010 Characterization of Ligand Effects on Physical Stability ofFormulations by the Thioflavine T Fluorescence Assay

Low physical stability of insulin formulations may lead to amyloidfibril formation, which is observed as well-ordered, thread-likemacromolecular structures in the sample eventually resulting in gelformation. This has traditionally been measured by visual inspection ofthe sample. However, the application of a small molecule indicator probeis much more preferable. Thioflavin T is such a probe and has a distinctfluorescence signature when binding to fibrils (or rather β-sheet richproteins) [Naiki et al. (1989) Anal. Biochem. 177, 244-249; LeVine(1999) Methods. Enzymol. 309, 274-284]. Its application to insulinfibrillation has recently been validated [Nielsen et al. (2001)Biochemistry 40, 6036-6046].

The time course for fibril formation can be described by a sigmoidalcurve with the following expression: $\begin{matrix}{F = {f_{i} + {m_{i}t} + \frac{f_{f} + {m_{f}t}}{1 + {\mathbb{e}}^{- {\lbrack{{({t - t_{0}})}/\tau}\rbrack}}}}} & {{Eq}.\quad(2)}\end{matrix}$Here, F is the ThT fluorescence at the time t. The constant t₀ is thetime needed to reach 50% of maximum fluorescence. The minimum andmaximum fluorescence is denoted f_(i) and f_(f), respectively, and theexpressions m_(i)t and m_(f)g describe the linear development of thebottom and top base lines. The two important parameters describingfibril formation are the lag-time calculated by t₀-2τ and the apparentrate constant k_(app)=1/τ.

Formation of a partially folded intermediate of the protein is suggestedas a general initiating mechanism for fibrillation. Few of thoseintermediates nucleate to form a template onto which furtherintermediates may assembly and the fibrillation is initiated. Thelag-time corresponds to the interval in which the critical mass ofnucleus is built up and the apparent rate constant is the rate withwhich the fibril itself is formed.

In accordance with this mechanism, insulin needs to dissociate to itsmonomeric form before a partially folded intermediate may be formed.Keeping insulin on a multimeric form may therefore result in increasedphysical stability. Ligands binding to the insulin hexamer zinc siteshould stabilize the hexameric form and draw the equilibrium evenfurther away from the monomeric form. Hence, an increased physicalstability could be achieved.

Sample Preparation

Insulin formulations were prepared freshly before each assay fromappropriate stock solutions. Typical final concentrations were 0.6 mMhuman insulin or insulin aspart analogue, 0.2 mM ZnAc, 30 mM phenol, 10mM Tris pH 8. ThT was added from a 1 mM stock solution in water to afinal concentration of 1 μM. The formulations were typically prepared indouble concentration and mixed with an equal volume of test compound inappropriate concentration in 4% DMSO, 10 mM Tris pH 8.

Alternatively, insulin aspart formulations (100 U/ml) from theproduction line were used directly. ThT was added to 1 μM and DMSOcontaining test compound in appropriate concentration to 2%.

Sample aliquots of 200 μl were placed in a 96 well microtiter plate(Packard OptiPlate™-96, white polystyrene). Usually, eight replica ofeach sample (corresponding to one test 373 compound concentration) wasplaced in one column of wells. The plate was sealed with Scotch Pad(Qiagen).

Control experiments for possible test compound quenching of the ThTemission were carried out using human insulin without Zn²⁺ and phenoli.e. in a non-hexameric configuration. Hence, the fibrillation processas well as the ThT emission should be unaffected by the presence of testcompound, unless it quenched the ThT signal.

Incubation and Fluorescence Measurement

Temperature incubation, shaking and measurement of the ThT fluorescencewere done in a Fluoroskan Ascent FL fluorescence platereader (ThermoLabsystems). Temperature setting is possible up till 45° C., but usuallysat at 30° C. Heating was initiated at first measurement. The orbitalshaking is selectable up till 1200 rpm, but adjusted to 960 rpm in allthe presented data with an amplitude of 1 mm.

Fluorescence measurement was done using excitation trough a 444 nmfilter and measurement of emission through a 485 nm filter. Each run wasinitiated by a measurement and intervals between measurements wereusually 20 min. The plate was shaken and heated as adjusted between eachmeasurement. The assay time was regulated by the number of measurementsand the interval in between. Usually the plate was measured 46 timeswith 20 min between, i.e. over 15 hours.

Data Handling

The measurement points were saved in Microsoft Excel format for furtherprocessing and curve drawing and fitting was performed using GraphPadPrism. The background emission from ThT in the absence of fibrils wasnegligible. Some test compounds had background fluorescence under theapplied experimental conditions. This was eliminated by subtracting themean value of the first measurement from the data set for this testcompound. The data points are shown with standard deviation.

The data set may be fitted to Eq. (2). However, since the stabilizingeffect of the test compounds/ligands were so significant that a fullsigmoid curve was not obtained during the usual assay time, curvefitting to such a data set would be imprecise and hence meaningless.

Only data obtained in the same experiment (i.e. samples on the sameplate) are presented in the same graph.

Examples & Results

The various ligands are shown below with structure and affinity towardsthe zinc site as measured by the TZD-assay described in “AnalyticalMethods”. K_(d)(app) Reference Example Compound (nM) A 533

383 C 462

58 D 738

171 E 68

23 F 756

3 G 1

3879 H 76

82 I 759

23

The ThT assays of various combinations of insulin formulations andligands are shown in FIG. 1-8.

Addition of ligands improves the physical stability of insulinformulations. This holds for human insulin formulations (see FIG. 1) aswell as insulin aspart formulations (rest of data set).

The improved stability can be obtained by using various compound classesas zinc site anchor, e.g. benzothriazoles (G, FIG. 1), naphthosalicylicacids (A, FIG. 2), thiazolidine-diones (E, FIGS. 4, 7; C, FIG. 2; H,FIGS. 6, 8) and tetrazoles (D, FIG. 3; F, FIG. 8; I, FIG. 5).

Increased affinity of the ligand results in higher stability of theformulation. Compare the effect of the weakest binding ligand in 2 mM(G, FIG. 1) with the effect on an insulin aspart formulation of 0.5 mM E(FIG. 4). Also compare the effects of similar concentrations of A and C(FIG. 2); and of D (FIG. 3) and E (FIG. 4) on insulin aspartformulations.

Increasing the concentration of ligand tends to improve thestabilization (see FIGS. 1, 3, 4, 5, 6). In some instants, morepronounced effects are seen with the ligand in slight molar excess tothe zinc sites, see FIGS. 4, 6, whereas it seems to plateau around thestoichiometric concentration in other instances (FIGS. 3, 5).

Of the presented ligands, A, C, D, E, F were tested in a disappearanceassay for the effect on release of insulin aspart from a subcutaneousinject site. Surprisingly, the ligands had no effect on the insulinaspart disappearance. In a very limited way, this can be mimicked in theThT assay by increasing the assay temperature to 37° C. (see FIGS. 7,8). The stabilizing effect is somewhat attenuated, e.g. compare E at 30°C. (FIG. 4) and 37° C. (FIG. 7), and H (FIG. 6 and 8). The ligand withhighest affinity (F) has the most stabilizing effect at 37° C. (FIG. 8).

Example 1011 Retention of Fast Absorption Characteristics ofFormulations Stabilized by Addition of His^(B)10 Zn²⁺-Site Ligands

Formulations of the present invention were characterized by thedisappearance rate from the subcutaneous depot following injection inpigs. Formulations of B28 Asp human insulin containing A14Tyr(¹²⁵I) B28Asp human insulin were followed with an external γ-counter (Ribel etal., The pig as a model for subcutaneous absorption in man. In:Serrano-Ritos & Lefebre (Eds.): Diabetes (1985) proceedings ot the12^(th) congress of the international diabetes federation, Madrid,Spain, 1985 (Excerpta Medica, Amsterdam (1986) 891-896. Formulations ofInsulin Aspart (0.6 mM, U100) containing 0.3 mM Zn²⁺, 30 mM phenol, 2 mMphosphate buffer, and 1.6% glycerol, pH 7.4, were compared with thecorresponding formulations containing 0.3 mM of the ligands shown below:where T_(50%) is the time when 50% ot the A14Tyr(¹²⁵I) B28 Asp insulinhas disappeared from the site of injection and K_(d) is the affinity ofthe ligand as measured by the TZD-assay described in “Analyticalmethods” below. It is evident that the stabilizing ligands do not affectthe fast absorption properties of the formulations K_(d) (app) Example #Compound T50% (nM) reference 1.3 ± 0.3  A 533

1.0 ± 0.23 383 B 476

1.1 ± 0.37 68 C 462

0.9 ± 0.19 58 D 738

1.3 ± 0.36 171 E 68

1.2 ± 0.41 23 F 756

1.2 ± 0.27 3

Example 1012

Reference Experiment

The chemical stability of insulin formulations of the invention wascharacterised by HPLC (RPC, reverse phase chromatography and SEC, sizeexclusion chromatography). As reference, insulin formulated withoutligands of the invention but with 0.3% DMSO was also investigated andshown below:

FIG. 10. Reverse phase chromatography of formulated human insulin with 3Zn²⁺ per hexamer, 30 mM phenol, 150 mM mannitol, 3 mM phosphoric acid,sodium hydroxide to pH 7.4 and 0.3% DMSO corresponding to 3 ligands perhexamer at start (upper panel) and after storage for 2 weeks at 37° C.(lower panel): Preservatives before 20 min., “hydrophilic derivatives”(desamido-insulins) 20 min to main top insulin, “hydrophobic derivatives1” main top to 64 min., and “hydrophobic derivatives 2” (insulin dimers)after 64 min.

Storage in HPLC 1 ml vials at 45° C. (5 d), 37° C. (2 w), 30° C. (6 w),25° C. (10 w), 15° C. (30 w) gave about the same increase oftransformation products correlating to an increase in reactionsconstants of a factor 3-4 per 10 degree.

RPC (reverse phase chromatography) on Waters SymmetryShield RP₈ column,150×4.6 mm and 3.5 μm, eluted by A: 0.2 M sodium sulfate+0.04 M sodiumphosphate pH 7.2+10% acetonitrile and isocratically (i) or a gradient(g) of B: 70% acetonitrile [minutes/% B(i/g): 0/19, 21/24(i)(suddenchange), 51/24(i), 81/39(g), 81.1/0(i), 82.3/19(i)] at flow of 0.9mL/min and 30° C.

SEC (size exclusion chromatography) on Waters insulin HMWP column,300×7.8 mm, eluted by 15:20:65 of acetic acid: acetonitrile: arginine 1g/L at flow of 1 mL/min and ambient temperature. RPC SEC % formed/yearhphil hphob1 hphob2 dimer 45° C. 153.3 47.5 23.4 21.9 37° C. 57.2 15.65.20 6.24 30° C. 24.5 4.16 1.30 2.08 25° C. 14.2 2.13 0.68 1.09 15° C.4.12 0.43 0.22 0.31 5° predicted (1.001) (0.066) (0.027) (0.052)

The chemical stability of insulin formulations of the invention waslikewise characterised by HPLC (RPC, reverse phase chromatography andSEC, size exclusion chromatography). Compared to the reference theformulations of the invention were shown to be more chemically stable.

Example 1013

Chemical stability of insulin formulated with the compound of example533, 7-bromo-3-hydroxy-2-naphthoic acid:

FIG. 11. Reverse phase chromatography of formulated human insulin asdescribed for the reference example and added 3 ligands of Example 533and 3 Zn²⁺ per hexamer at start (upper panel) and after storage for 2weeks at 37° C. (lower panel): Preservatives before 20 min.,“hydrophilic derivatives” (desamido-insulins) 20 min to main topinsulin, “hydrophobic derivatives 1” main top to 64 min., and“hydrophobic derivatives 2” (insulin dimers) after 64 min.

Storage in HPLC 1 ml vials at 45° C. (5 d), 37° C. (2 w), 30° C. (6 w),25° C. (10 w), 15° C. (30 w) will give about the same increase intransformation products correlating to an increase in reaction constantsof a factor 3-4 per 10 degrees.

RPC (reverse phase chromatography) on Waters SymmetryShield RP₈ column,150×4.6 mm and 3.5 μm, eluted by A: 0.2 M sodium sulfate+0.04 M sodiumphosphate pH 7.2+10% acetonitrile and isocratically (i) or a gradient(g) of B: 70% acetonitrile [minutes/% B(i/g): 0/19, 21/24(i)(suddenchange), 51/24(i), 81/39(g), 81.1/0(i), 82.3/19(i)] at flow of 0.9mL/min and 30° C.

SEC (size exclusion chromatography) on Waters insulin HMWP column,300×7.8 mm, eluted by 15:20:65 of acetic acid: acetonitrile:arginine 1g/L at flow of 1 mL/min and ambient temperature. RPC SEC % formed/yearhphil hphob1 hphob2 dimer 45° C. 30.7 62.1 23.4 26.3 37° C. 12.5 22.47.02 7.02 30° C. 6.76 6.42 2.25 2.86 25° C. 4.06 5.67 1.46 1.61 15° C.1.80 0.85 0.42 0.45 5° predicted (0.55) (0.19) (0.079) (0.087)

Example 1014

Chemical stability of insulin formulated with the compound of Example462, 3-[4-2,4-dioxothiazolidin-5-ylidenemethyl)phenyl]acrylic acid:

FIG. 12. Reverse phase chromatography of formulated human insulin asdescribed for the reference example and added 3 ligands of example 462and 3 Zn²⁺ per hexamer at start (upper panel) and after storage for 2weeks at 37° C. (lower panel): Preservatives before 20 min.,“hydrophilic derivatives” (desamido-insulins) 20 min to main topinsulin, “hydrophobic derivatives 1” main top to 64 min., and“hydrophobic derivatives 2” (insulin dimers) after 64 min.

Storage in HPLC 1 ml vials at 45° C. (5 d), 37° C. (2 w), 30° C. (6 w),25° C. (10 w), 15° C. (30 w) will give about the same increase intransformation products correlating to an increase in reaction constantsof a factor 3-4 per 10 degrees.

RPC (reverse phase chromatography) on Waters SymmetryShield RP₈ column,150×4.6 mm and 3.5 μm, eluted by A: 0.2 M sodium sulfate+0.04 M sodiumphosphate pH 7.2+10% acetonitrile and isocratically (i) or a gradient(g) of B: 70% acetonitrile [minutes/% B(i/g): 0/19, 21/24(i)(suddenchange), 51/24(i), 81/39(g), 81.1/0(i), 82.3/19(i)] at flow of 0.9mL/min and 30° C.

SEC (size exclusion chromatography) on Waters insulin HMWP column,300×7.8 mm, eluted by 15:20:65 of acetic acid: acetonitrile:arginine 1g/L at flow of 1 mL/min and ambient temperature. RPC SEC % formed/yearhphil hphob1 hphob2 Dimer 45° C. 20.4 43.8 17.5 21.2 37° C. 9.88 19.54.68 6.24 30° C. 4.07 4.42 1.65 2.17 25° C. 2.60 6.14 0.78 1.09 15° C.1.02 1.28 0.38 0.28 5° predicted (0.293) (0.336) (0.062) (0.048)

Example 1015

Chemical stability of insulin formulated with the compound of example461, [3-(2,4-Dioxothiazolidin-5-ylidenemethyl)phenoxy]acetic acid:

FIG. 13. Reverse phase chromatography of formulated human insulin added3 ligands (#) and 3 Zn per hexamer at start and storage of 2 w 37° C.:Preservatives before 20 min., “hydrophilic derivatives”(desamido-insulins) 20 min to main top insulin, “hydrophobic derivatives1” main top to 64 min., and “hydrophobic derivatives 2” (insulin dimers)after 64 min.

Storage in HPLC 1 ml vials at 45° C. (5 d), 37° C. (2 w), 30° C. (6 w),25° C. (10 w), 15° C. (30 w) will give about the same increase of 0.7%hfil, 0.6% hfob1, 0.3% hfob2 and 0.3% dimer solution 1, correlating toQ₁₀ of 3 below 30° C. and 4 at higher temperature for ref.

RPC (reverse phase chromatography) on Waters SymmetryShield RP₈ column,150×4.6 mm and 3.5 μm, eluted by A: 0.2 M sodium sulfate+0.04 M sodiumphosphate pH 7.2+10% acetonitrile and isocratically (i) or a gradient(g) of B: 70% acetonitrile [minutes/% B(i/g): 0/19, 21/24(i)(suddenchange), 51/24(i), 81/39(g), 81.1/0(i), 82.3/19(i)] at flow of 0.9mL/min and 30° C.

SEC (size exclusion chromatography) on Waters insulin HMWP column,300×7.8 mm, eluted by 15:20:65 of acetic acid: acetonitrile:arginine 1g/L at flow of 1 mL/min and ambient temperature. RPC SEC % formed/yearhphil hphob1 hphob2 dimer 45° C. 29.9 52.6 23.4 23.4 37° C. 11.2 20.07.02 6.50 30° C. 5.12 7.11 1.99 2.34 25° C. 2.86 4.78 0.99 1.20 15° C.1.14 0.67 0.29 0.33 5° predicted (0.287) (0.153) (0.044) (0.057)

Example 1016

Chemical stability of insulin formulated with the compound of example70, 5-(4-Diethylaminobenzylidene)thiazolidine-2,4-dione

FIG. 14. Reverse phase chromatography of formulated human insulin added3 ligands (#) and 3 Zn per hexamer at start and storage of 2 w 37° C.:Preservatives before 20 min., “hydrophilic derivatives”(desamido-insulins) 20 min to main top insulin, “hydrophobic derivatives1” main top to 64 min., and “hydrophobic derivatives 2” (insulin dimers)after 64 min.

Storage in HPLC 1 ml vials at 45° C. (5 d), 37° C. (2 w), 30° C. (6 w),25° C. (10 w), 15° C. (30 w) will give about the same increase of 0.7%hfil, 0.6% hfob1, 0.3% hfob2 and 0.3% dimer solution 1, correlating toQ₁₀ of 3 below 30° C. and 4 at higher temperature for ref.

RPC (reverse phase chromatography) on Waters SymmetryShield RP₈ column,150×4.6 mm and 3.5 μm, eluted by A: 0.2 M sodium sulfate+0.04 M sodiumphosphate pH 7.2+10% acetonitrile and isocratically (i) or a gradient(g) of B: 70% acetonitrile [minutes/% B(i/g): 0/19, 21/24(i)(suddenchange), 51/24(i), 81/39(g), 81.1/0(i), 82.3/19(i)] at flow of 0.9mL/min and 30° C.

SEC (size exclusion chromatography) on Waters insulin HMWP column,300×7.8 mm, eluted by 15:20:65 of acetic acid: acetonitrile:arginine 1g/L at flow of 1 mL/min and ambient temperature. RPC SEC % formed/yearhphil hphob1 hphob2 dimer 45° C. 56.2 78.8 27.0 29.2 37° C. 23.7 14.86.50 8.84 30° C. 12.1 6.94 3.03 3.55 25° C. 6.08 4.99 0.94 2.24 15° C.1.95 1.09 0.42 0.69 5° predicted (0.54) (0.22) (0.064) (0.15)

Analytical Methods

Assays to quantify the binding affinity of ligands to the metal site ofthe insulin R₆ hexamers:

4H3N-Assay:

The binding affinity of ligands to the metal site of insulin R₆ hexamersare measured in a UV/vis based displacement assay. The UV/vis spectrumof 3-hydroxy-4-nitro benzoic acid (4H3N) which is a known ligand for themetal site of insulin R₆ shows a shift in absorption maximum upondisplacement from the metal site to the solution (Huang et al., 1997,Biochemistry 36, 9878-9888). Titration of a ligand to a solution ofinsulin R₆ hexamers with 4H3N mounted in the metal site allows thebinding affinity of these ligands to be determined following thereduction of absorption at 444 nm.

A stock solution with the following composition 0.2 mM human insulin,0.067 mM Zn-acetate, 40 mM phenol, 0.101 mM 4H3N is prepared in a 10 mLquantum as described below. Buffer is always 50 mM tris buffer adjustedto pH=8.0 with NaOH/ClO₄ ⁻.

-   -   1000 μL of 2.0 mM human insulin in buffer    -   66.7 μL of 10 mM Zn-acetate in buffer    -   800 μL of 500 mM phenol in H₂O    -   201 μL of 4H3N in H₂O    -   7.93 ml buffer

The ligand is dissolved in DMSO to a concentration of 20 mM.

The ligand solution is titrated to a cuvette containing 2 mL stocksolution and after each addition the UV/vis spectrum is measured. Thetitration points are listed in Table 3 below.

TABLE 3

ligand ligand addition conc. dilution (μl) (mM) factor 1 0.010 1.0005 10.020 1.0010 1 0.030 1.0015 2 0.050 1.0025 5 0.100 1.0050 10 0.1981.0100 20 0.392 1.0200 20 0.583 1.0300 20 0.769 1.0400 20 0.952 1.0500

The UV/vis spectra resulting from a titration of the compound3-hydroxy-2-naphthoic acid is shown in FIG. 5. Inserted in the upperright corner is the absorbance at 444 nm vs. the concentration ofligand.

The following equation is fitted to these datapoints to determine thetwo parameters K_(D)(obs), the observed dissociation constant, andabs_(max) the absorbance at maximal ligand concentration.abs([ligand]_(free))=(abs _(max)*[ligand]_(free))/(K_(D)(obs)+[ligand]_(free))

The observed dissociation constant is recalculated to obtain theapparent dissociation constantK _(D)(app)=K _(D)(obs)/(1+[4H3N]/K _(4H3N))The value of K_(4H3N)=50 μM is taken from Huang et al., 1997,Biochemistry 36, 9878-9888.TZD-Assay:

The binding affinity of ligands to the metal site of insulin R₆ hexamersare measured in a fluorescense based displacement assay. Thefluorescence of 5-(4-dimethylaminobenzylidene)thiazolidine-2,4-dione(TZD) which is a ligand for the metal site of insulin R₆ is quenchedupon displacement from the metal site to the solution. Titration of aligand to a stock solution of insulin R₆ hexamers with this compoundmounted in the metal site allows the binding affinity of these ligandsto be determined measuring the fluorescence at 455 nm upon excitation at410 nm.

Preparation

Stock solution: 0.02 mM human insulin, 0.007 mM Zn-acetate, 40 mMphenol, 0.01 mM TZD in 50 mM tris buffer adjusted to pH=8.0 withNaOH/ClO₄ ⁻.

The ligand is dissolved in DMSO to a concentration of 5 mM and added inaliquots to the stock solution to final concentrations of 0-250 □M.

Measurements

Fluorescence measurements were carried out on a Perkin ElmerSpectrofluorometer LS50B. T main absorption band was excited at 410 nmand emission was detected at 455 nm. The resolution was 10 nm and 2.5 nmfor excitation and emission, respectively.

Data Analysis

This equation is fitted to the datapointsΔF(455 nm))=ΔF _(max)* [ligand]_(free)/(K _(D)(app)*(1+[TZD]/K_(TZD))+[ligand]_(free)))K_(D)(app) is the apparent dissociation constant and F_(max) is thefluorescence at maximal ligand concentration. The value of K_(TZD) ismeasured separately to 230 nM

Two different fitting-procedures can be used. One in which bothparameters, K_(D)(app) and F_(max), are adjusted to best fit the dataand a second in which the value of F_(max) is fixed (F_(max)=1) and onlyK_(D)(app) is adjusted. The given data are from the second fittingprocedure. The Solver module of Microsoft Excel can be used to generatethe fits from the data points.

1. A pharmaceutical composition comprising insulin and a zinc-bindingligand which reversibly binds to a His^(B10) Zn²⁺ site of an insulinhexamer, wherein the ligand is selected from the group consisting ofbenzotriazoles, 3-hydroxy 2-naphthoic acids, salicylic acids,tetrazoles, thiazolidinediones, 5-mercaptotetrazoles, pyrimidinetriones,or 4-cyano-1,2,3-triazoles, or enantiomers, diastereomers, racemicmixtures, tautomers, or salts thereof with a pharmaceutically acceptableacid or base.
 2. A pharmaceutical composition according to claim 1wherein the zinc-binding ligand is

wherein X is ═O, ═S or ═NH Y is —S—, —O— or —NH— R¹, R^(1A) and R⁴ areindependently selected from hydrogen or C₁-C₆-alkyl, R² and R^(2A) arehydrogen or C₁-C₆-alkyl or aryl, R¹ and R² may optionally be combined toform a double bond, R^(1A) and R^(2A) may optionally be combined to forma double bond, R³, R^(3A) and R⁵ are independently selected fromhydrogen, halogen, aryl optionally substituted with one or moresubstituents independently selected from R¹⁶, C₁-C₆-alkyl, or—C(O)NR¹¹R¹², A, A¹ and B are independently selected from C₁-C₆-alkyl,aryl, aryl-C₁-C₆-alkyl, —NR¹¹-aryl, aryl-C₂-C₆-alkenyl or heteroaryl,wherein the alkyl or alkenyl is optionally substituted with one or moresubstituents independently selected from R⁶ and the aryl or heteroarylis optionally substituted with up to four substituents R⁷, R⁸, R⁹, andR¹⁰, A and R³ may be connected through one or two valence bonds, B andR⁵ may be connected through one or two valence bonds, R⁶ isindependently selected from halogen, —CN, —CF₃, —OCF₃, aryl, —COOH and—NH₂, R⁷, R⁸, R⁹ and R¹⁰ are independently selected from hydrogen,halogen, —CN, —CH₂CN, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂,—S(O)₂CF₃, —OS(O)₂CF₃, —SCF₃, —NO₂, —OR¹¹, —NR¹¹R¹², —SR¹¹,—NR¹¹S(O)₂R¹², —S(O)₂NR¹¹R¹², —S(O)NR¹¹R¹², —S(O)R¹¹, —S(O)₂R¹¹,—OS(O)₂R¹¹, —C(O)NR¹¹R¹², —OC(O)NR¹¹R¹², —NR¹¹C(O)R¹², —CH₂C(O)NR¹¹R¹²,—OC₁-C₆-alkyl-C(O)NR¹¹R¹², —CH₂OR¹¹, —CH₂OC(O)R¹¹, —CH₂NR¹¹R¹²,—OC(O)R¹¹, —OC₁-C₁₅-alkyl-C(O)OR¹¹, —OC₁-C₆-alkyl-OR¹¹,—SC₁-C₆-alkyl-C(O)OR¹¹, —C₂-C₆-alkenyl-C(═O)OR¹¹,—NR¹¹—C(═O)—C₁-C₆-alkyl-C(═O)OR¹¹, —NR¹¹—C(═O)—C₁-C₆-alkenyl-C(═O)OR¹¹,—C(O)OR¹¹, C(O)R¹¹, or —C₂-C₆-alkenyl-C(═O)R¹¹, ═O, or—C₂-C₆-alkenyl-C(═O)—NR¹¹R¹², C₁-C₆-alkyl, C₂-C₆-alkenyl orC₂-C₆-alkynyl, each of which may optionally be substituted with one ormore substituents independently selected from R¹³, aryl, aryloxy,aryloxycarbonyl, aroyl, arylsulfanyl, aryl-C₁-C₆-alkoxy,aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, aroyl-C₂-C₆-alkenyl,aryl-C₂-C₆-alkynyl, heteroaryl, heteroaryl-C₁-C₆-alkyl,heteroaryl-C₂-C₆-alkenyl, heteroaryl-C₂-C₆-alkynyl, or C₃-C₆ cycloalkyl,of which each cyclic moiety may optionally be substituted with one ormore substituents independently selected from R¹⁴, R¹¹ and R¹² areindependently selected from hydrogen, OH, C₁-C₂₀-alkyl, aryl-C₁-C₆-alkylor aryl, wherein the alkyl groups may optionally be substituted with oneor more substituents independently selected from R¹⁵, and the arylgroups may optionally be substituted one or more substituentsindependently selected from R¹⁶; R¹¹ and R¹² when attached to the samenitrogen atom may form a 3 to 8 membered heterocyclic ring with the saidnitrogen atom, the heterocyclic ring optionally containing one or twofurther heteroatoms selected from nitrogen, oxygen and sulphur, andoptionally containing one or two double bonds, R¹³ is independentlyselected from halogen, —CN, —CF₃, —OCF₃, —OR¹¹, —C(O)OR¹¹, —NR¹¹R¹², and—C(O)NR¹¹R¹², R¹⁴ is independently selected from halogen, —C(O)OR¹¹,—CH₂C(O)OR¹¹, —CH₂OR¹¹, —CN, —CF₃, —OCF₃, —NO₂, —OR¹¹, —NR¹¹R¹²,—NR¹¹C(O)R¹¹, —S(O)₂R¹¹, aryl and C₁-C₆-alkyl, R¹⁵ is independentlyselected from halogen, —CN, —CF₃, ═O, —OCF₃, —OC₁-C₆-alkyl,—C(O)OC₁—C₆-alkyl, —COOH and —NH₂, R¹⁶ is independently selected fromhalogen, —C(O)OC₁-C₆-alkyl, —COOH, —CN, —CF₃, —OCF₃, —NO₂, —OH,—OC₁-C₆-alkyl, —NH₂, C(═O) or C₁-C₆-alkyl, or any enantiomer,diastereomer, including a racemic mixture, tautomer as well as a saltthereof with a pharmaceutically acceptable acid or base.
 3. Apharmaceutical composition according to claim 2 wherein X is ═O or ═S.4. A pharmaceutical composition according to claim 3 wherein X is ═O. 5.A pharmaceutical composition according to claim 3 wherein X is ═S.
 6. Apharmaceutical composition according to claim 2 wherein Y is —O— or —S—.7. A pharmaceutical composition according to claim 6 wherein Y is —O—.8. A pharmaceutical composition according to claim 6 wherein Y is —NH—.9. A pharmaceutical composition according to claim 6 wherein Y is —S—.10. A pharmaceutical composition according to claim 2 wherein A is aryloptionally substituted with up to four substituents, R⁷, R⁸, R⁹, and R¹⁰which may be the same or different.
 11. A pharmaceutical compositionaccording to claim 10 wherein A is selected from ArG1 optionallysubstituted with up to four substituents, R⁷, R⁸, R⁹, and R¹⁰ which maybe the same or different.
 12. A pharmaceutical composition according toclaim 11 wherein A is phenyl or naphtyl optionally substituted with upto four substituents, R⁷, R⁸, R⁹, and R¹⁰ which may be the same ordifferent.
 13. A pharmaceutical composition according to claim 12wherein A is


14. A pharmaceutical composition according to claim 12 wherein A isphenyl.
 15. A pharmaceutical composition according to claim 2 wherein Ais heteroaryl optionally substituted with up to four substituents, R⁷,R⁸, R⁹, and R¹⁰ which may be the same or different.
 16. A pharmaceuticalcomposition according to claim 15 wherein A is selected from Het1optionally substituted with up to four substituents, R⁷, R⁸, R⁹, and R¹⁰which may be the same or different.
 17. A pharmaceutical compositionaccording to claim 16 wherein A is selected from Het2 optionallysubstituted with up to four substituents, R⁷, R⁸, R⁹, and R¹⁰ which maybe the same or different.
 18. A pharmaceutical composition according toclaim 17 wherein A is selected from Het3 optionally substituted with upto four substituents, R⁷, R⁸, R⁹, and R¹⁰ which may be the same ordifferent.
 19. A pharmaceutical composition according to claim 18wherein A is selected from the group consisting of indolyl,benzofuranyl, quinolyl, furyl, thienyl, or pyrrolyl, wherein eachheteroaryl may optionally substituted with up to four substituents, R⁷,R⁸, R⁹, and R¹⁰ which may be the same or different.
 20. A pharmaceuticalcomposition according to claim 18 wherein A is benzofuranyl optionallysubstituted with up to four substituents R⁷, R⁸, R⁹, and R¹⁰ which maybe the same or different.
 21. A pharmaceutical composition according toclaim 20 wherein A is


22. A pharmaceutical composition according to claim 18 wherein A iscarbazolyl optionally substituted with up to four substituents R⁷, R⁸,R⁹, and R¹⁰ which may be the same or different.
 23. A pharmaceuticalcomposition according to claim 22 wherein A is


24. A pharmaceutical composition according to claim 18 wherein A isquinolyl optionally substituted with up to four substituents R⁷, R⁸, R⁹,and R¹⁰ which may be the same or different.
 25. A pharmaceuticalcomposition according to claim 24 wherein A is


26. A pharmaceutical composition according to claim 18 wherein A isindolyl optionally substituted with up to four substituents R⁷, R⁸, R⁹,and R¹⁰ which may be the same or different.
 27. A pharmaceuticalcomposition according to claim 26 wherein A is


28. A pharmaceutical composition according to claim 2 wherein R¹ ishydrogen.
 29. A pharmaceutical composition according to claim 2 whereinR² is hydrogen.
 30. A pharmaceutical composition according to claim 2wherein R¹ and R² are combined to form a double bond.
 31. Apharmaceutical composition according to claim 2 wherein R³ isC₁-C₆-alkyl, halogen, or C(O)NR¹⁶R¹⁷.
 32. A pharmaceutical compositionaccording to claim 31 wherein R³ is C₁-C₆-alkyl or C(O)NR¹⁶R¹⁷.
 33. Apharmaceutical composition according to claim 32 wherein R³ is methyl.34. A pharmaceutical composition according to claim 2 wherein B isphenyl optionally substituted with up to four substituents, R⁷, R⁸, R⁹,and R¹⁰ which may be the same or different.
 35. A pharmaceuticalcomposition according to claim 2 wherein R⁴ is hydrogen.
 36. Apharmaceutical composition according to claim 2 wherein R⁵ is hydrogen.37. A pharmaceutical composition according to claim 2 wherein R⁶ isaryl.
 38. A pharmaceutical composition according to claim 37 wherein R⁶is phenyl.
 39. A pharmaceutical composition according to claim 2 whereinR⁷, R⁸, R⁹ and R¹⁰ are independently selected from hydrogen, halogen,—NO₂, —R¹¹, —NR¹¹R¹², —SR¹¹, —NR¹¹S(O)₂R¹², —S(O)₂NR¹¹R¹², —S(O)NR¹¹R¹²,—S(O)R¹¹, —S(O)₂R¹¹, —OS(O)₂ R¹¹, —NR¹¹C(O)R¹², —CH₂OR¹¹, —CH₂OC(O)R¹¹,—CH₂NR¹¹R¹², —OC(O)R¹¹, —OC₁-C₆-alkyl-C(O)OR¹¹,—OC₁-C₆-alkyl-C(O)NR¹¹R¹², —OC₁-C₆-alkyl-OR¹¹, —SC₁-C₆-alkyl-C(O)OR¹¹,—C₂-C₆-alkenyl-C(═O)OR¹¹, —C(O)OR¹¹, or —C₂-C₆-alkenyl-C(═O)R¹¹,C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, which may each optionallybe substituted with one or more substituents independently selected fromR¹³ aryl, aryloxy, aroyl, arylsulfanyl, aryl-C₁-C₆-alkoxy,aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, aroyl-C₂-C₆-alkenyl,aryl-C₂-C₆-alkynyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, wherein each ofthe cyclic moieties optionally may be substituted with one or moresubstituents independently selected from R¹⁴
 40. A pharmaceuticalcomposition according to claim 39 wherein R⁷, R⁸, R⁹ and R¹⁰ areindependently selected from hydrogen, halogen, —NO₂, —OR¹¹, —NR¹¹R¹²,—SR¹¹, —S(O)₂R¹¹, —OS(O)₂ R¹¹, —CH₂OC(O)R¹¹, —OC(O)R¹¹,—OC₁-C₆-alkyl-C(O)OR¹¹, —OC₁-C₆-alkyl-OR¹¹, —SC₁-C₆-alkyl-C(O)OR¹¹,—C(O)OR¹¹, or —C₂-C₆-alkenyl-C(═O)R¹¹, C₁-C₆-alkyl or C₁-C₆-alkenylwhich may each optionally be substituted with one or more substituentsindependently selected from R¹³ aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy,aryl-C₁-C₆-alkyl, heteroaryl, of which each of the cyclic moietiesoptionally may be substituted with one or more substituentsindependently selected from R¹⁴
 41. A pharmaceutical compositionaccording to claim 40 wherein R⁷, R⁸, R⁹ and R¹⁰ are independentlyselected from hydrogen, halogen, —NO₂, —OR¹¹, —NR¹¹R¹², —SR¹¹,—S(O)₂R¹¹, —OS(O)₂ R¹¹, —CH₂OC(O)R¹¹, —OC(O)R¹¹, —OC₁-C₆-alkyl-C(O)OR¹¹,—OC₁-C₆-alkyl-OR¹¹, —SC₁-C₆-alkyl-C(O)OR¹¹, —C(O)OR¹¹, or—C₂-C₆-alkenyl-C(═O)R¹¹, C₁-C₆-alkyl or C₁-C₆— which may each optionallybe substituted with one or more substituents independently selected fromR¹³ aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl,heteroaryl, of which each of the cyclic moieties optionally may besubstituted with one or more substituents independently selected fromR¹⁴
 42. A pharmaceutical composition according to claim 41 wherein R⁷,R⁸, R⁹ and R¹⁰ are independently selected from hydrogen, halogen, —OR¹¹,—OC₁-C₆-alkyl-C(O)OR¹¹, or —C(O)OR¹¹, C₁-C₆-alkyl which may eachoptionally be substituted with one or more substituents independentlyselected from R¹³ aryl, aryloxy, aryl-C₁-C₆-alkoxy, of which each of thecyclic moieties optionally may be substituted with one or moresubstituents independently selected from R¹⁴.
 43. A pharmaceuticalcomposition according to claim 42 wherein R⁷, R⁸, R⁹ and R¹⁰ areindependently selected from hydrogen, halogen, —OR¹¹,—OC₁-C₆-alkyl-C(O)OR¹¹, or —C(O)OR¹¹, C₁-C₆-alkyl which may eachoptionally be substituted with one or more substituents independentlyselected from R¹³ ArG1, ArG1oxy, ArG1-C₁-C₆-alkoxy, of which each of thecyclic moieties optionally may be substituted with one or moresubstituents independently selected from R¹⁴.
 44. A pharmaceuticalcomposition according to claim 43 wherein R⁷, R⁸, R⁹ and R¹⁰ areindependently selected from hydrogen, halogen, —OR¹¹,—OC₁-C₆-alkyl-C(O)OR¹¹, or —C(O)OR¹¹, C₁-C₆-alkyl which may optionallybe substituted with one or more substituents independently selected fromR¹³ phenyl, phenyloxy, phenyl-C₁-C₆-alkoxy, wherein each of the cyclicmoieties optionally may be substituted with one or more substituentsindependently selected from R¹⁴.
 45. A pharmaceutical compositionaccording to claim 2 wherein R¹¹ and R¹² are independently selected fromhydrogen, C₁-C₂₀-alkyl, aryl or aryl-C₁-C₆-alkyl, wherein the alkylgroups may optionally be substituted with one or more substituentsindependently selected from R¹⁵, and the aryl groups may optionally besubstituted one or more substituents independently selected from R¹⁶;R¹¹ and R¹² when attached to the same nitrogen atom may form a 3 to 8membered heterocyclic ring with the nitrogen atom, the heterocyclic ringoptionally containing one or two further heteroatoms selected fromnitrogen, oxygen and sulphur, and optionally containing one or twodouble bonds.
 46. A pharmaceutical composition according to claim 45wherein R¹¹ and R¹² are independently selected from hydrogen,C₁-C₂₀-alkyl, aryl or aryl-C₁-C₆-alkyl, wherein the alkyl groups mayoptionally be substituted with one or more substituents independentlyselected from R¹⁵, and the aryl groups may optionally be substituted oneor more substituents independently selected from R¹⁶.
 47. Apharmaceutical composition according to claim 46 wherein R¹¹ and R¹² areindependently selected from phenyl or phenyl-C₁-C₆-alkyl.
 48. Apharmaceutical composition according to claim 46 wherein one or both ofR¹¹ and R¹² are methyl.
 49. A pharmaceutical composition according toclaim 2 wherein R¹³ is independently selected from halogen, CF₃, OR¹¹ orNR¹¹R¹².
 50. A pharmaceutical composition according to claim 49 whereinR¹³ is independently selected from halogen or OR¹¹.
 51. A pharmaceuticalcomposition according to claim 50 wherein R¹³ is OR¹¹.
 52. Apharmaceutical composition according to claim 2 wherein R¹⁴ isindependently selected from halogen, —C(O)OR¹¹, —CN, —CF₃, —OR¹¹,S(O)₂R¹¹, and C₁-C₆-alkyl.
 53. A pharmaceutical composition according toclaim 52 wherein R¹⁴ is independently selected from halogen, —C(O)OR¹¹,or —OR¹¹.
 54. A pharmaceutical composition according to claim 2 whereinR¹⁵ is independently selected from halogen, —CN, —CF₃,—C(O)OC₁-C₆-alkyl,and —COOH.
 55. A pharmaceutical composition accordingto claim 54 wherein R¹⁵ is independently selected from halogen or—C(O)OC₁-C₆-alkyl.
 56. A pharmaceutical composition according to claim 2wherein R¹⁶ is independently selected from halogen, —C(O)OC₁-C₆-alkyl,—COOH, —NO₂, —OC₁-C₆-alkyl, —NH₂, C(═O) or C₁-C₆-alkyl.
 57. Apharmaceutical composition according to claim 56 wherein R¹⁶ isindependently selected from halogen, —C(O)OC₁-C₆-alkyl, —COOH, —NO₂, orC₁-C₆-alkyl.
 58. A pharmaceutical composition according to claim 1wherein the zinc-binding ligand is

wherein R¹⁹ is hydrogen or C₁-C₆-alkyl, R²⁰ is hydrogen or C₁-C₆-alkyl,D, D¹ and F are a valence bond, C₁-C₆-alkylene or C₁-C₆-alkenyleneoptionally substituted with one or more substituents independentlyselected from R⁷², R⁷² is independently selected from hydroxy,C₁-C₆-alkyl, or aryl, E is C₁-C₆-alkyl, aryl or heteroaryl, wherein thearyl or heteroaryl is optionally substituted with up to threesubstituents R²¹, R²² and R²³, G and G¹ are C₁-C₆-alkyl, aryl orheteroaryl, wherein the aryl or heteroaryl is optionally substitutedwith up to three substituents R²⁴, R²⁵ and R²⁶, R¹⁷, R¹⁸, R²¹, R²², R²³,R²⁴, R²⁵ and R²⁶ are independently selected from hydrogen, halogen, —CN,—CH₂CN, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃,—SCF₃, —NO₂, ═O, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷S(O)₂R²⁸, —S(O)₂NR²⁷R²⁸,—S(O)NR²⁷R²⁸, —S(O)R²⁷, —S(O)₂R²⁷, —C(O)NR²⁷R²⁸, —OC(O)NR²⁷R²⁸,—NR²⁷C(O)R²⁸, —NR²⁷C(O)OR²⁸, —CH₂C(O)NR²⁷R²⁸, —OCH₂C(O)NR²⁷R²⁸,—CH₂OR²⁷, —CH₂NR²⁷R²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷,—SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷, —NR²⁷—C(═O)—C₁-C₆-alkyl-C(═O)OR²⁷, —NR²⁷—C(═O)—C₁-C₆-alkenyl-C(═O)OR²⁷,—C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷,C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, which may optionally besubstituted with one or more substituents independently selected fromR²⁹, aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C₁-C₆-alkoxy,aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl,heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl orheteroaryl-C₂-C₆-alkynyl, of which the cyclic moieties optionally may besubstituted with one or more substituents selected from R³⁰, R²⁷ and R²⁸are independently selected from hydrogen, C₁-C₆-alkyl, aryl-C₁-C₆-alkylor aryl, or R²⁷ and R²⁸ when attached to the same nitrogen atom togetherwith the said nitrogen atom may form a 3 to 8 membered heterocyclic ringoptionally containing one or two further heteroatoms selected fromnitrogen, oxygen and sulphur, and optionally containing one or twodouble bonds, R²⁹ is independently selected from halogen, —CN, —CF₃,—OCF₃, —OR²⁷, and —NR²⁷R²⁸, R³⁰ is independently selected from halogen,—C(O)OR²⁷, —CN, —CF₃, —OCF₃, —NO₂, —OR²⁷, —NR²⁷R²⁸ and C₁-C₆-alkyl, orany enantiomer, diastereomer, including a racemic mixture, tautomer aswell as a salt thereof with a pharmaceutically acceptable acid or base.59. A pharmaceutical composition according to claim 58 wherein D is avalence bond.
 60. A pharmaceutical composition according to claim 58wherein D is C₁-C₆-alkylene optionally substituted with one or morehydroxy, C₁-C₆-alkyl, or aryl.
 61. A pharmaceutical compositionaccording to claim 58 wherein E is aryl or heteroaryl, wherein the arylor heteroaryl is optionally substituted with up to three substituentsindependently selected from R²¹, R²² and R²³.
 62. A pharmaceuticalcomposition according to claim 61 wherein E is aryl optionallysubstituted with up to three substituents independently selected fromR²¹, R²² and R²³.
 63. A pharmaceutical composition according to claim 62wherein E is selected from ArG1 and optionally substituted with up tothree substituents independently selected from R²¹, R²² and R²³.
 64. Apharmaceutical composition according to claim 63 wherein E is phenyloptionally substituted with up to three substituents independentlyselected from R²¹, R²² and R²³.
 65. A pharmaceutical compositionaccording to claim 64 wherein the zinc-binding ligand is


66. A pharmaceutical composition according to claim 58 wherein R²¹, R²²and R²³ are independently selected from hydrogen, halogen, —CHF₂, —CF₃,—OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —SCF₃, —NO₂, —OR²⁷, —NR²⁷R²⁸, —SR²⁷,—C(O)NR²⁷R²⁸, —OC(O)NR²⁷R²⁸, —NR²⁷C(O)R²⁸, —NR²⁷C(O)OR²⁸,—CH₂C(O)NR²⁷R²⁸, —OCH₂C(O)NR²⁷R²⁸, —CH₂OR²⁷, —CH₂NR²⁷R²⁸, —OC(O)R²⁷,—OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷,—C₂-C₆-alkenyl-C(═O)OR²⁷, —NR²⁷—C(═O)—C₁-C₆-alkyl-C(═O)OR²⁷,—NR²⁷—C(═O)—C₁-C₆-alkenyl-C(═O)OR²⁷—, —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷,—C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷, C₁-C₆-alkyl, C₂-C₆-alkenyl orC₂-C₆-alkynyl, which may optionally be substituted with one or moresubstituents independently selected from R²⁹ aryl, aryloxy,aryloxycarbonyl, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl,aryl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl,heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl orheteroaryl-C₂-C₆-alkynyl, of which the cyclic moieties optionally may besubstituted with one or more substituents selected from R³⁰.
 67. Apharmaceutical composition according to claim 66 wherein R²¹, R²² andR²³ are independently selected from hydrogen, halogen, —OCF₃, —OR²⁷,—NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸, —NR²⁷C(O)OR²⁸, —OC(O)R²⁷,—OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷,—C₂-C₆-alkenyl-C(═O)OR²⁷, —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷,—C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷, C₁-C₆-alkyl optionally substitutedwith one or more substituents independently selected from R²⁹ aryl,aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, heteroaryl,heteroaryl-C₁-C₆-alkyl, of which the cyclic moieties optionally may besubstituted with one or more substituents selected from R³⁰.
 68. Apharmaceutical composition according to claim 67 wherein R²¹, R²² andR²³ are independently selected from hydrogen, halogen, —OCF₃, —OR²⁷,—NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸, —NR²⁷C(O)OR²⁸, —OC(O)R²⁷,—OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷,—C₂-C₆-alkenyl-C(═O)OR²⁷, —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷,—C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷, methyl, ethyl propyl optionallysubstituted with one or more substituents independently selected fromR²⁹ aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl,heteroaryl, heteroaryl-C₁-C₆-alkyl of which the cyclic moietiesoptionally may be substituted with one or more substituents selectedfrom R³⁰.
 69. A pharmaceutical composition according to claim 68 whereinR²¹, R²² and R²³ are independently selected from hydrogen, halogen,—OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸, —NR²⁷C(O)OR²⁸, —OC(O)R²⁷,—C₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷,—C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷,methyl, ethyl propyl optionally substituted with one or moresubstituents independently selected from R²⁹ ArG1, ArG1-O—, ArG1-C(O)—,ArG1-C₁-C₆-alkoxy, ArG₁-C₁-C₆-alkyl, Het3, Het3-C₁-C₆-alkyl of which thecyclic moieties optionally may be substituted with one or moresubstituents selected from R³⁰.
 70. A pharmaceutical compositionaccording to claim 69 wherein R²¹, R²² and R²³ are independentlyselected from hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷,—NR²⁷C(O)R²⁸, —NR²⁷C(O)R²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷,—SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷,—C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷,C₁-C₆-alkyl optionally substituted with one or more substituentsindependently selected from R²⁹ phenyl, phenyloxy, phenyl-C₁-C₆-alkoxy,phenyl-C₁-C₆-alkyl, of which the cyclic moieties optionally may besubstituted with one or more substituents selected from R³⁰.
 71. Apharmaceutical composition according to claim 58 wherein R¹⁹ is hydrogenor methyl.
 72. A pharmaceutical composition according to claim 71wherein R¹⁹ is hydrogen.
 73. A pharmaceutical composition according toclaim 58 wherein R²⁷ is Hydrogen, C₁-C₆-alkyl or aryl.
 74. Apharmaceutical composition according to claim 73 wherein R²⁷ is hydrogenor C₁-C₆-alkyl.
 75. A pharmaceutical composition according to claim 58wherein R²⁸ is hydrogen or C₁-C₆-alkyl.
 76. A pharmaceutical compositionaccording to claim 58 wherein F is a valence bond.
 77. A pharmaceuticalcomposition according to claim 58 wherein F is C₁-C₆-alkylene optionallysubstituted with one or more hydroxy, C₁-C₆-alkyl, or aryl.
 78. Apharmaceutical composition according to claim 58 wherein G isC₁-C₆-alkyl or aryl, wherein the aryl is optionally substituted with upto three substituents R²⁴, R²⁵ and R²⁶.
 79. A pharmaceutical compositionaccording to claim 58 wherein G is C₁-C₆-alkyl or ArG1, wherein the arylis optionally substituted with up to three substituents R²⁴, R²⁵ andR²⁶.
 80. A pharmaceutical composition according to claim 78 wherein G isC₁-C₆-alkyl.
 81. A pharmaceutical composition according to claim 80wherein G is phenyl optionally substituted with up to three substituentsR²⁴, R²⁵ and R²⁶.
 82. A pharmaceutical composition according to claim 58wherein R²⁴, R²⁵ and R²⁶ are independently selected from hydrogen,halogen, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —SCF₃, —NO₂,—OR²⁷, —NR²⁷R²⁸, —SR²⁷, —C(O)NR²⁷R²⁸, —OC(O)NR²⁷R²⁸, —NR²⁷C(O)R²⁸,—NR²⁷C(O)OR²⁸, —CH₂C(O)NR²⁷R²⁸, —OCH₂C(O)NR²⁷R²⁸, —CH₂OR²⁷, —CH₂NR²⁷R²⁸,—OC(O)R²⁷, —C₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷,—C₂-C₆-alkenyl-C(═O)OR²⁷, —NR²⁷—C(═O)—C₁-C₆-alkyl-C(═O)OR²⁷,—NR²⁷-C(═O)-C₁-C₆-alkenyl-C(═O)OR²⁷—, —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷,—C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷, C₁-C₆-alkyl, C₂-C₆-alkenyl orC₂-C₆-alkynyl, which may optionally be substituted with one or moresubstituents independently selected from R²⁹ aryl, aryloxy,aryloxycarbonyl, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl,aryl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl,heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl orheteroaryl-C₂-C₆-alkynyl, of which the cyclic moieties optionally may besubstituted with one or more substituents selected from R³⁰.
 83. Apharmaceutical composition according to claim 82 wherein R²⁴, R²⁵ andR²⁶ are independently selected from hydrogen, halogen, —OCF₃, —OR²⁷,—NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸, —NR²⁷C(O)OR²⁸, —OC(O)R²⁷,—OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷,—C₂-C₆-alkenyl-C(═O)OR²⁷, —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷,—C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷, C₁-C₆-alkyl, C₂-C₆-alkenyl orC₂-C₆-alkynyl, which may optionally be substituted with one or moresubstituents independently selected from R²⁹ aryl, aryloxy,aryloxycarbonyl, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl,aryl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl,heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl orheteroaryl-C₂-C₆-alkynyl, of which the cyclic moieties optionally may besubstituted with one or more substituents selected from R³⁰.
 84. Apharmaceutical composition according to claim 83 wherein R²⁴, R²⁵ andR²⁶ are independently selected from hydrogen, halogen, —OCF₃, —OR²⁷,—NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸, —NR²⁷C(O)OR²⁸, —OC(O)R²⁷,—OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷,—C₁-C₆-alkenyl-C(═O)OR²⁷, —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷,—C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷, C₁-C₆-alkyl optionally substitutedwith one or more substituents independently selected from R²⁹ aryl,aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, heteroaryl,heteroaryl-C₁-C₆-alkyl, of which the cyclic moieties optionally may besubstituted with one or more substituents selected from R³⁰.
 85. Apharmaceutical composition according to claim 84 wherein R²¹, R²² andR²³ are independently selected from hydrogen, halogen, —OCF₃, —OR²⁷,—NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸, —NR²⁷C(O)OR²⁸, —OC(O)R²⁷,—OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷,—C₂-C₆-alkenyl-C(═O)OR²⁷, —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷,—C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷, methyl, ethyl propyl optionallysubstituted with one or more substituents independently selected fromR²⁹ ArG1, ArG1-O—, ArG1-C(O)—, ArG1-C₁-C₆-alkoxy, ArG1-C₁-C₆-alkyl,Het3, Het3-C₁-C₆-alkyl of which the cyclic moieties optionally may besubstituted with one or more substituents selected from R³⁰.
 86. Apharmaceutical composition according to claim 85 wherein R²¹, R²² andR²³ are independently selected from hydrogen, halogen, —OCF₃, —OR²⁷,—NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸, —NR²⁷C(O)OR²⁸, —OC(O)R²⁷,—OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷,—C₂-C₆-alkenyl-C(═O)OR²⁷, —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷,—C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷, methyl, ethyl propyl optionallysubstituted with one or more substituents independently selected fromR²⁹ ArG1, ArG1-O—, ArG1-C(O)—, ArG1-C₁-C₆-alkoxy, ArG1-C₁-C₆-alkyl,Het3, Het3-C₁-C₆-alkyl of which the cyclic moieties optionally may besubstituted with one or more substituents selected from R³⁰.
 87. Apharmaceutical composition according to claim 86 wherein R²¹, R²² andR²³ are independently selected from hydrogen, halogen, —OCF₃, —OR²⁷,—NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸, —NR²⁷C(O)OR²⁸, —OC(O)R²⁷,—OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷,—C₂-C₆-alkenyl-C(═O)OR²⁷, —C(═O)NR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷,—C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷, methyl, ethyl propyl optionallysubstituted with one or more substituents independently selected fromR²⁹ ArG1, ArG1-O—, ArG1-C₁-C₆-alkoxy, ArG1-C₁-C₆-alkyl, of which thecyclic moieties optionally may be substituted with one or moresubstituents selected from R³⁰.
 88. A pharmaceutical compositionaccording to claim 58 wherein R²⁰ is hydrogen or methyl.
 89. Apharmaceutical composition according to claim 88 wherein R²⁰ ishydrogen.
 90. A pharmaceutical composition according to claim 58 whereinR²⁷ is hydrogen, C₁-C₆-alkyl or aryl.
 91. A pharmaceutical compositionaccording to claim 90 wherein R²⁷ is hydrogen or C₁-C₆-alkyl or ArG1.92. A pharmaceutical composition according to claim 91 wherein R²⁷ ishydrogen or C₁-C₆-alkyl.
 93. A pharmaceutical composition according toclaim 58 wherein R²⁸ is hydrogen or C₁-C₆-alkyl.
 94. A pharmaceuticalcomposition according to claim 58 wherein R¹⁷ and R¹⁸ are independentlyselected from hydrogen, halogen, —CN, —CF₃, —OCF₃, —NO₂, —OR²⁷,—NR²⁷R²⁸, —SR²⁷, —S(O)R²⁷, —S(O)₂R²⁷, —C(O)NR²⁷R²⁸, —CH₂OR²⁷, —OC(O)R²⁷,—OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷, or —C(O)OR²⁷,C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, optionally substituted withone or more substituents independently selected from R²⁹ aryl, aryloxy,aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, heteroaryl,heteroaryl-C₁-C₆-alkyl, of which the cyclic moieties optionally may besubstituted with one or more substituents selected from R³⁰.
 95. Apharmaceutical composition according to claim 94 wherein R¹⁷ and R¹⁸ areindependently selected from hydrogen, halogen, —CN, —CF₃, —NO₂, —OR²⁷,—NR²⁷R²⁸, or —C(O)OR²⁷, C₁-C₆-alkyl optionally substituted with one ormore substituents independently selected from R²⁹ aryl, aryloxy, aroyl,aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, heteroaryl, heteroaryl-C₁-C₆-alkyl,of which the cyclic moieties optionally may be substituted with one ormore substituents selected from R³⁰.
 96. A pharmaceutical compositionaccording to claim 95 wherein R¹⁷ and R¹⁸ are independently selectedfrom hydrogen, halogen, —CN, —CF₃, —NO₂, —OR²⁷, —NR²⁷R²⁸, or —C(O)OR²⁷methyl, ethyl propyl optionally substituted with one or moresubstituents independently selected from R²⁹ aryl, aryloxy, aroyl,aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, heteroaryl, heteroaryl-C₁-C₆-alkylof which the cyclic moieties optionally may be substituted with one ormore substituents selected from R³⁰.
 97. A pharmaceutical compositionaccording to claim 96 wherein R¹⁷ and R¹⁸ are independently selectedfrom hydrogen, halogen, —CN, —CF₃, —NO₂, —OR² , —NR²⁷R²⁸, or —C(O)OR²⁷methyl, ethyl propyl optionally substituted with one or moresubstituents independently selected from R²⁹ ArG1, ArG1-O—, ArG1-C(O)—,ArG1-C₁-C₆-alkoxy, ArG1-C₁-C₆-alkyl, Het3, Het3-C₁-C₆-alkyl of which thecyclic moieties optionally may be substituted with one or moresubstituents selected from R³⁰.
 98. A pharmaceutical compositionaccording to claim 97 wherein R¹⁷ and R¹⁸ are independently selectedfrom hydrogen, halogen, —CN, —CF₃, —NO₂, —OR² , —NR²⁷R²⁸, or —C(O)OR²⁷C₁-C₆-alkyl optionally substituted with one or more substituentsindependently selected from R²⁹ phenyl, phenyloxy, phenyl-C₁-C₆-alkoxy,phenyl-C₁-C₆-alkyl, of which the cyclic moieties optionally may besubstituted with one or more substituents selected from R³⁰.
 99. Apharmaceutical composition according to claim 58 wherein R²⁷ is hydrogenor C₁-C₆-alkyl.
 100. A pharmaceutical composition according to claim 99wherein R²⁷ is hydrogen, methyl or ethyl.
 101. A pharmaceuticalcomposition according to claim 58 wherein R²⁸ is hydrogen orC₁-C₆-alkyl.
 102. A pharmaceutical composition according to claim 101wherein R²⁸ is hydrogen, methyl or ethyl.
 103. A pharmaceuticalcomposition according to claim 58 wherein R⁷² is —OH or phenyl.
 104. Apharmaceutical composition according to claim 58 wherein thezinc-binding ligand is


105. A pharmaceutical composition according to claim 1 wherein thezinc-binding ligand is of the form H—I-J wherein H is

wherein the phenyl, naphthalene or benzocarbazole rings are optionallysubstituted with one or more substituents independently selected fromR³¹ I is selected from a valence bond, —CH₂N(R³²)— or —SO₂N(R³³)—,

wherein Z¹ is S(O)₂ or CH₂, Z² is —NH—, —O— or —S—, and n is 1 or 2, Jis C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, which may eachoptionally be substituted with one or more substituents selected fromR³⁴, Aryl, aryloxy, aryl-oxycarbonyl-, aroyl, aryl-C₁-C₆-alkoxy-,aryl-C₁-C₆-alkyl-, aryl-C₂-C₆-alkenyl-, aryl-C₂-C₆-alkynyl-, heteroaryl,heteroaryl-C₁-C₆-alkyl-, heteroaryl-C₂-C₆-alkenyl- orheteroaryl-C₂-C₆-alkynyl-, wherein the cyclic moieties are optionallysubstituted with one or more substituents selected from R³⁷, Hydrogen,R³¹ is independently selected from hydrogen, halogen, —CN, —CH₂CN,—CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —SCF₃, —NO₂,—OR³⁵, —C(O)R³⁵, —NR³⁵R³⁶, —SR³⁵, —NR³⁵S(O)₂R³⁶, —S(O)₂NR³⁵R³⁶,—S(O)NR³⁵R³⁶, —S(O)R³⁵, —S(O)₂R³⁵, —C(O)R³⁵R³⁶, —OC(O)NR³⁵R³⁶,—NR³⁵C(O)R³⁶, —CH₂C(O)NR³⁵R³⁶, —OCH₂C(O)NR³⁵R³⁶, —CH₂OR³⁵, —CH₂NR³⁵R³⁶,—OC(O)R³⁵, —OC₁-C₆-alkyl-C(O)OR³⁵, —SC₁-C₆-alkyl-C(O)OR³⁵—C₂-C₆-alkenyl-C(═O)OR³⁵, —NR³⁵—C(═O)—C₁-C₆-alkyl-C(═O)OR³⁵,—NR³⁵—C(═O)—C₁-C₆-alkenyl-C(═O)OR³⁵—, C₁-C₆-alkyl, C₁-C₆-alkanoyl or—C(O)OR³⁵, R³² and R³³ are independently selected from hydrogen,C₁-C₆-alkyl or C₁-C₆-alkanoyl, R³⁴ is independently selected fromhalogen, —CN, —CF₃, —OCF₃, —OR³⁵, and —NR³⁵R³⁶, R³⁵ and R³⁶ areindependently selected from hydrogen, C₁-C₆-alkyl, aryl-C₁-C₆-alkyl oraryl, or R³⁵ and R³⁶ when attached to the same nitrogen atom togetherwith the said nitrogen atom may form a 3 to 8 membered heterocyclic ringoptionally containing one or two further heteroatoms selected fromnitrogen, oxygen and sulphur, and optionally containing one or twodouble bonds, R³⁷ is independently selected from halogen, —C(O)OR³⁵,—C(O)H, —CN, —CF₃, —OCF₃, —NO₂, —OR³⁵, —NR³⁵R³⁶, C₁-C₆-alkyl orC₁-C₆-alkanoyl, or any enantiomer, diastereomer, racemic mixture,tautomer, or salt thereof with a pharmaceutically acceptable acid orbase.
 106. A pharmaceutical composition according to claim 105 whereinthe zinc-binding ligand is of the form H—I-J, wherein H is

wherein the phenyl, naphthalene or benzocarbazole rings are optionallysubstituted with one or more substituents independently selected fromR³¹, I is selected from a valence bond, —CH₂N(R³²)— or —SO₂N(R³³)—,

wherein Z¹ is S(O)₂ or CH₂, Z² is N, —O— or —S—, and n is 1 or 2, J isC₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, which may each optionallybe substituted with one or more substituents selected from R³⁴, Aryl,aryloxy, aryl-oxycarbonyl-, aroyl, aryl-C₁-C₆-alkoxy-,aryl-C₁-C₆-alkyl-, aryl-C₂-C₆-alkenyl-, aryl-C₂-C₆-alkynyl-, heteroaryl,heteroaryl-C₁-C₆-alkyl-, heteroaryl-C₂-C₆-alkenyl- orheteroaryl-C₂-C₆-alkynyl-, wherein the cyclic moieties are optionallysubstituted with one or more substituents selected from R³⁷, hydrogen,R³¹ is independently selected from hydrogen, halogen, —CN, —CH₂CN,—CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —SCF₃, —NO₂,—OR³⁵, —C(O)R³⁵, —NR³⁵R³⁶, —SR³⁵, —NR³⁵S(O)₂R³⁶, —S(O)₂NR³⁵R³⁶,—S(O)NR³⁵R³⁶, —S(O)R³⁵, —S(O)₂R³⁵, —C(O)NR³⁵R³⁶, —OC(O)NR³⁵R³⁶,—NR³⁵C(O)R³⁶, —CH₂C(O)NR³⁵R³⁶, —OCH₂C(O)NR ³⁵R³⁶, —CH₂OR³⁵, —CH₂NR³⁵R³⁶,—OC(O)R³⁵, —OC₁-C₆-alkyl-C(O)OR³⁵, —SC₁-C₆-alkyl-C(O)OR³⁵—C₂-C₆-alkenyl-C(═O)OR³⁵, —NR³⁵—C(═O)—C₁-C₆-alkyl-C(═O)OR³⁵,—NR³⁵—C(═O)—C₁-C₆-alkenyl-C(═O)OR³⁵—, C₁-C₆-alkyl, C₁-C₆-alkanoyl or—C(O)OR³⁵, R³² and R³³ are independently selected from hydrogen,C₁-C₆-alkyl or C₁-C₆-alkanoyl, R³⁴ is independently selected fromhalogen, —CN, —CF₃, —OCF₃, —OR³⁵, and —NR³⁵R³⁶, R³⁵ and R³⁶ areindependently selected from hydrogen, C₁-C₆-alkyl, aryl-C₁-C₆-alkyl oraryl, or R³⁵ and R³⁶ when attached to the same nitrogen atom togetherwith the nitrogen atom may form a 3 to 8 membered heterocyclic ringoptionally containing one or two further heteroatoms selected fromnitrogen, oxygen and sulphur, and optionally containing one or twodouble bonds, R³⁷ is independently selected from halogen, —C(O)OR³⁵,—C(O)H, —CN, —CF₃, —OCF₃, —NO₂, —OR³⁵, —NR³⁵R³⁶, C₁-C₆-alkyl orC₁-C₆-alkanoyl, or any enantiomer, diastereomer, racemic mixture,tautomer, or salt thereof with a pharmaceutically acceptable acid orbase, with the proviso that R³¹ and J cannot both be hydrogen.
 107. Apharmaceutical composition according to claim 105 wherein H is


108. A pharmaceutical composition according to claim 107 wherein H is


109. A pharmaceutical composition according to claim 107 wherein H is


110. A pharmaceutical composition according to claim 105 wherein I is avalence bond, —CH₂N(R³²)—, or —SO₂N(R³³)—.
 111. A pharmaceuticalcomposition according to claim 110 wherein I is a valence bond.
 112. Apharmaceutical composition according to claim 105 wherein J is hydrogen,C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, which may optionally besubstituted with one or more substituents selected from halogen, —CN,—CF₃, —OCF₃, —OR³⁵, and —NR³⁵R³⁶, aryl, or heteroaryl, wherein thecyclic moieties are optionally substituted with one or more substituentsindependently selected from R³⁷.
 113. A pharmaceutical compositionaccording to claim 112 wherein J is hydrogen, aryl or heteroaryl,wherein the cyclic moieties are optionally substituted with one or moresubstituents independently selected from R³⁷.
 114. A pharmaceuticalcomposition according to claim 112 wherein J is hydrogen, ArG1 or Het3,wherein the cyclic moieties are optionally substituted with one or moresubstituents independently selected from R³⁷.
 115. A pharmaceuticalcomposition according to claim 114 wherein J is hydrogen, phenyl ornaphthyl optionally substituted with one or more substituentsindependently selected from R³⁷.
 116. A pharmaceutical compositionaccording to claim 115 wherein J is hydrogen.
 117. A pharmaceuticalcomposition according to claim 105 wherein R³² and R³³ are independentlyselected from hydrogen or C₁-C₆-alkyl.
 118. A pharmaceutical compositionaccording to claim 105 wherein R³⁴ is hydrogen, halogen, —CN, —CF₃,—OCF₃, —SCF₃, —NO₂, —OR³⁵, —C(O)R³⁵, —NR³⁵R³⁶, —SR³⁵, —C(O)NR³⁵R³⁶,—OC(O)NR³⁵R³⁶, —NR³⁵C(O)R³⁶, —OC(O)R³⁵, —OC₁-C₆-alkyl-C(O)OR³⁵,—SC₁-C₆-alkyl-C(O)OR³⁵ or —C(O)OR³⁵.
 119. A pharmaceutical compositionaccording to claim 118 wherein R³⁴ is hydrogen, halogen, —CF₃, —NO₂,—OR³⁵, —NR³⁵R³⁶, —SR³⁵, —NR³⁵C(O)R³⁶, or —C(O)OR³⁵.
 120. Apharmaceutical composition according to claim 119 wherein R³⁴ ishydrogen, halogen, —CF₃, —NO₂, —OR³⁵, —NR³⁵R³⁶, or —NR³⁵C(O)R³⁶.
 121. Apharmaceutical composition according to claim 120 wherein R³⁴ ishydrogen, halogen, or —OR³⁵.
 122. A pharmaceutical composition accordingto claim 105 wherein R³⁵ and R³⁶ are independently selected fromhydrogen, C₁-C₆-alkyl, or aryl.
 123. A pharmaceutical compositionaccording to claim 122 wherein R³⁵ and R³⁶ are independently selectedfrom hydrogen or C₁-C₆-alkyl.
 124. A pharmaceutical compositionaccording to claim 105 wherein R³⁷ is halogen, —C(O)OR³⁵, —CN, —CF₃,—OR³⁵, —NR³⁵R³⁶, C₁-C₆-alkyl or C₁-C₆-alkanoyl.
 125. A pharmaceuticalcomposition according to claim 124 wherein R³⁷ is halogen, —C(O)OR³⁵,—OR³⁵, —NR³⁵R³⁶, C₁-C₆-alkyl or C₁-C₆-alkanoyl.
 126. A pharmaceuticalcomposition according to claim 125 wherein R³⁷ is halogen, —C(O)OR³⁵ or—OR³⁵.
 127. A pharmaceutical composition according to claim 1 whereinthe zinc-binding ligand is

wherein K is a valence bond, C₁-C₆-alkylene, —NH—C(═O)—U—,—C₁-C₆-alkyl-S—, —C₁-C₆-alkyl-O—, —C(═O)—, or —C(═O)—NH—, wherein anyC₁-C₆-alkyl moiety is optionally substituted with R³⁸, U is a valencebond, C₁-C₆-alkenylene, —C₁-C₆-alkyl-O— or C₁-C₆-alkylene wherein anyC₁-C₆-alkyl moiety is optionally substituted with C₁-C₆-alkyl, R³⁸ isC₁-C₆-alkyl, aryl, wherein the alkyl or aryl moieties are optionallysubstituted with one or more substituents independently selected fromR³⁹, R³⁹ is independently selected from halogen, cyano, nitro, amino, Mis a valence bond, arylene or heteroarylene, wherein the aryl orheteroaryl moieties are optionally substituted with one or moresubstituents independently selected from R⁴⁰, R⁴⁰ is selected fromhydrogen, halogen, —CN, —CH₂CN, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃,—OCF₂CHF₂, —S(O)₂CF₃, —OS(O)₂CF₃, —SCF₃, —NO₂, —OR⁴¹, —NR⁴¹R⁴², —SR⁴¹,—NR S(O)₂R⁴², —S(O)₂NR⁴¹R⁴², —S(O)NR⁴¹R⁴², —S(O)R⁴¹, —S(O)₂R⁴¹, —OS(O)₂R⁴¹, —C(O)NR⁴¹ R⁴², —OC(O)NR⁴¹R⁴², —NR⁴¹C(O)R⁴², —CH₂C(O)NR⁴¹R⁴²,—OC₁-C₆-alkyl-C(O)NR⁴¹R⁴², —CH₂OR⁴¹, —CH₂OC(O)R⁴¹, —CH₂NR⁴¹R⁴²,—OC(O)R⁴¹, 13 OC₁-C₆-alkyl-C(O)OR⁴¹, —OC₁-C₆-alkyl-OR⁴¹,—S—C₁-C₆-alkyl-C(O)OR⁴¹, —C₂-C₆-alkenyl-C(═O)OR⁴¹,—NR⁴¹—C(═O)—C₁-C₆-alkyl-C(═O)OR⁴¹, —NR⁴¹—C(═O)—C₁-C₆-alkenyl-C(═O)OR⁴¹,—C(O)OR⁴¹, —C₂-C₆-alkenyl-C(═O)R⁴¹, ═O, —NH—C(═O)—O—C₁-C₆-alkyl, or—NH—C(═O)—C(═O)—O—C₁-C₆-alkyl, C₁-C₆-alkyl, C₂-C₆-alkenyl orC₂-C₆-alkynyl, which may each optionally be substituted with one or moresubstituents selected from R⁴³, aryl, aryloxy, aryloxycarbonyl, aroyl,arylsulfanyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl,aroyl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl,heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl orheteroaryl-C₂-C₆-alkynyl, wherein the cyclic moieties optionally may besubstituted with one or more substituents selected from R⁴⁴, R⁴¹ and R⁴²are independently selected from hydrogen, —OH, C₁-C₆-alkyl,C₁-C₆-alkenyl, aryl-C₁-C₆-alkyl or aryl, wherein the alkyl moieties mayoptionally be substituted with one or more substituents independentlyselected from R⁴⁵, and the aryl moieties may optionally be substitutedwith one or more substituents independently selected from R⁴⁶; R⁴¹ andR⁴² when attached to the same nitrogen atom may form a 3 to 8 memberedheterocyclic ring with the said nitrogen atom, the heterocyclic ringoptionally containing one or two further heteroatoms selected fromnitrogen, oxygen and sulphur, and optionally containing one or twodouble bonds, R⁴³ is independently selected from halogen, —CN, —CF₃,—OCF₃, —OR⁴¹, and —NR⁴¹R⁴² R⁴⁴ is independently selected from halogen,—C(O)OR⁴¹, —CH₂C(O)OR⁴¹, —CH₂OR⁴¹, —CN, —CF₃, —OCF₃, —NO₂, —OR⁴¹,—NR⁴¹R⁴² and C₁-C₆-alkyl, R⁴⁵ is independently selected from halogen,—CN, —CF₃, —OCF₃, —O—C₁-C₆-alkyl, —C(O)—O—C₁-C₆-alkyl, —COOH and —NH₂,R⁴⁶ is independently selected from halogen, —C(O)OC₁-C₆-alkyl, —COOH,—CN, —CF₃, —OCF₃, —NO₂, —OH, —OC₁-C₆-alkyl, —NH₂, C(═O) or C₁-C₆-alkyl,Q is a valence bond, C₁-C₆-alkylene, —C₁-C₆-alkyl-O—, —C₁-C₆-alkyl-NH—,—NH—C₁-C₆-alkyl, —NH—C(═O)—, —C(═O)—NH—, —O—C₁-C₆-alkyl, —C(═O)—, or—C₁-C₆-alkyl-C(═O)—N(R⁴⁷)— wherein the alkyl moieties are optionallysubstituted with one or more substituents independently selected fromR⁴⁸, R⁴⁷ and R⁴⁸ are independently selected from hydrogen, C₁-C₆-alkyl,aryl optionally substituted with one or more R⁴⁹, R⁴⁹ is independentlyselected from halogen and —COOH, T is hydrogen, C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkyloxy-carbonyl, wherein thealkyl, alkenyl and alkynyl moieties are optionally substituted with oneor more substituents independently selected from R⁵⁰, aryl, aryloxy,aryloxy-carbonyl, aryl-C₁-C₆-alkyl, aroyl, aryl-C₁-C₆-alkoxy,aryl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkyny-, heteroaryl,heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl,heteroaryl-C₂-C₆-alkynyl, wherein any alkyl, alkenyl, alkynyl, aryl andheteroaryl moiety is optionally substituted with one or moresubstituents independently selected from R⁵⁰, R⁵⁰ is C₁-C₆-alkyl,C₁-C₆-alkoxy, aryl, aryloxy, aryl-C₁-C₆-alkoxy,—C(═O)—NH—C₁-C₆-alkyl-aryl, —C(═O)—NR^(50A)—C₁-C₆-alkyl,—C(═O)—NH—(CH₂CH₂O)_(m)C₁-C₆-alkyl-COOH, heteroaryl,heteroaryl-C₁-C₆-alkoxy, —C₁-C₆-alkyl-COOH, —O—C₁-C₆-alkyl-COOH,—S(O)₂R⁵¹, —C₂-C₆-alkenyl-COOH, —OR⁵¹, —NO₂, halogen, —COOH, —CF₃, —CN,═O, —N(R⁵¹R⁵²), wherein m is 1, 2, 3 or 4, and wherein the aryl orheteroaryl moieties are optionally substituted with one or more R⁵³, andthe alkyl moieties are optionally substituted with one or more R^(50B).R^(50A) and R^(50B) are independently selected from —C(O)OC₁-C₆-alkyl,—COOH, —C₁-C₆-alkyl-C(O)OC₁-C₆-alkyl, —C₁-C₆-alkyl-COOH, or C₁-C₆-alkyl,R⁵¹ and R⁵² are independently selected from hydrogen and C₁-C₆-alkyl,R⁵³ is independently selected from C₁-C₆-alkyl, C₁-C₆-alkoxy,—C₁-C₆-alkyl-COOH, —C₂-C₆-alkenyl-COOH, —OR⁵¹, —NO₂, halogen, —COOH,—CF₃, —CN, or —N(R⁵¹R⁵²), or any enantiomer, diastereomer, racemicmixture, tautomer, or salt thereof with a pharmaceutically acceptableacid or base.
 128. A pharmaceutical composition according to claim 127wherein K is a valence bond, C₁-C₆-alkylene, —NH—C(═O)—U—,—C₁-C₆-alkyl-S—, —C₁-C₆-alkyl-O—, or —C(═O)—, wherein any C₁-C₆-alkylmoiety is optionally substituted with R³⁸.
 129. A pharmaceuticalcomposition according to claim 128 wherein K is a valence bond,C₁-C₆-alkylene, —NH—C(═O)—U—, —C₁-C₆-alkyl-S—, or —C₁-C₆-alkyl-O,wherein any C₁-C₆-alkyl moiety is optionally substituted with R³⁸. 130.A pharmaceutical composition according to claim 129 wherein K is avalence bond, C₁-C₆-alkylene, or —NH—C(═O)—U, wherein any C₁-C₆-alkylmoiety is optionally substituted with R³⁸.
 131. A pharmaceuticalcomposition according to claim 130 wherein K is a valence bond orC₁-C₆-alkylene, wherein any C₁-C₆-alkyl moiety is optionally substitutedwith R³⁸.
 132. A pharmaceutical composition according to claim 130wherein K is a valence bond or —NH—C(═O)—U.
 133. A pharmaceuticalcomposition according to claim 131 wherein K is a valence bond.
 134. Apharmaceutical composition according to claim 127 wherein U is a valencebond or —C₁-C₆-alkyl-O—.
 135. A pharmaceutical composition according toclaim 134 wherein U is a valence bond.
 136. A pharmaceutical compositionaccording to claim 127 wherein M is arylene or heteroarylene, whereinthe arylene or heteroarylene moieties are optionally substituted withone or more substituents independently selected from R⁴⁰.
 137. Apharmaceutical composition according to claim 136 wherein M is ArG1 orHet1, wherein the arylene or heteroarylene moieties are optionallysubstituted with one or more substituents independently selected fromR⁴⁰.
 138. A pharmaceutical composition according to claim 137 wherein Mis ArG1 or Het2, wherein the arylene or heteroarylene moieties areoptionally substituted with one or more substituents independentlyselected from R⁴⁰.
 139. A pharmaceutical composition according to claim138 wherein M is ArG1 or Het3, wherein the arylene or heteroarylenemoieties are optionally substituted with one or more substituentsindependently selected from R⁴⁰.
 140. A pharmaceutical compositionaccording to claim 139 wherein M is phenylene optionally substitutedwith one or more substituents independently selected from R⁴⁰.
 141. Apharmaceutical composition according to claim 139 wherein M isindolylene optionally substituted with one or more substituentsindependently selected from R⁴⁰.
 142. A pharmaceutical compositionaccording to claim 141 wherein M is


143. A pharmaceutical composition according to claim 139 wherein M iscarbazolylene optionally substituted with one or more substituentsindependently selected from R⁴⁰.
 144. A pharmaceutical compositionaccording to claim 143 wherein M is


145. A pharmaceutical composition according to claim 127 wherein R⁴⁰ isselected from hydrogen, halogen, —CN, —CF₃, —OCF₃, —NO₂, —OR⁴, —NR⁴¹R⁴²,—SR⁴¹, —S(O)₂R⁴¹, —NR⁴ C(O)R⁴², —OC₁-C₆-alkyl-C(O)NR⁴¹R⁴²,—C₂-C₆-alkenyl-C(═O)OR⁴¹, —C(O)OR⁴¹, ═O, —NH—C(═O)—O—C₁-C₆-alkyl, or—NH—C(═O)—C(═O)—O—C₁-C₆-alkyl, C₁-C₆-alkyl or C₂-C₆-alkenyl which mayeach optionally be substituted with one or more substituentsindependently selected from R⁴³, aryl, aryloxy, aryl-C₁-C₆-alkoxy,aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, heteroaryl,heteroaryl-C₁-C₆-alkyl, or heteroaryl-C₂-C₆-alkenyl, wherein the cyclicmoieties optionally may be substituted with one or more substituentsselected from R⁴⁴.
 146. A pharmaceutical composition according to claim145 wherein R⁴⁰ is selected from hydrogen, halogen, —CN, —CF₃, —OCF₃,—NO₂, —OR⁴¹, —NR⁴¹R⁴², —SR⁴¹, —S(O)₂R⁴¹, —NR⁴¹C(O)R⁴²,—OC₁-C₆-alkyl-C(O)NR⁴¹R⁴², —C₂-C₆-alkenyl-C(═O)OR⁴¹, —C(O)OR⁴¹, ═O,—NH—C(═O)—O—C₁-C₆-alkyl, or —NH—C(═O)—C(═O)—O—C₁-C₆-alkyl, C₁-C₆-alkylor C₂-C₆-alkenyl which may each optionally be substituted with one ormore substituents independently selected from R⁴³, ArG1, ArG1-O—,ArG1-C₁-C₆-alkoxy, ArG1-C₁-C₆-alkyl, ArG1-C₂-C₆-alkenyl, Het3,Het3-C₁-C₆-alkyl, or Het3-C₂-C₆-alkenyl, wherein the cyclic moietiesoptionally may be substituted with one or more substituents selectedfrom R⁴⁴.
 147. A pharmaceutical composition according to claim 146wherein R⁴⁰ is selected from hydrogen, halogen, —CF₃, —NO₂, —OR⁴¹,—NR⁴¹R⁴², —C(O)OR⁴¹, ═O, or —NR⁴¹C(O)R⁴², C₁-C₆-alkyl, and ArG1.
 148. Apharmaceutical composition according to claim 147 wherein R⁴⁰ ishydrogen.
 149. A pharmaceutical composition according to claim 147wherein R⁴⁰ is selected from Halogen, —NO₂, —OR⁴¹, —NR⁴¹R⁴², —C(O)OR⁴¹,or —NR⁴¹C(O)R⁴², Methyl, and Phenyl.
 150. A pharmaceutical compositionaccording to claim 127 wherein R⁴¹ and R⁴² are independently selectedfrom hydrogen, C₁-C₆-alkyl, or aryl, wherein the aryl moieties mayoptionally be substituted with halogen or —COOH.
 151. A pharmaceuticalcomposition according to claim 150 wherein R⁴¹ and R⁴² are independentlyselected from hydrogen, methyl, ethyl, or phenyl, wherein the phenylmoieties may optionally be substituted with halogen or —COOH.
 152. Apharmaceutical composition according to claim 127 wherein Q is a valencebond, C₁-C₆-alkylene, —C₁-C₆-alkyl-O—, —C₁-C₆-alkyl-NH—,—NH-C₁-C₆-alkyl, —NH—C(═O)—, —C(═O)—NH—, —O—C₁-C₆-alkyl, —C(═O)—, or—C₁-C₆-alkyl-C(═O)—N(R⁴⁷)— wherein the alkyl moieties are optionallysubstituted with one or more substituents independently selected fromR⁴⁸.
 153. A pharmaceutical composition according to claim 152 wherein Qis a valence bond, —CH₂—, —CH₂—CH₂—, —CH₂—O—, —CH₂—CH₂—O—, —CH₂—NH—,—CH₂—CH₂—NH—, —NH—CH₂—, —NH—CH₂—CH₂—, —NH—C(═O)—, —C(═O)—NH—, —O—CH₂—,—O—CH₂-CH₂—, or —C(═O)—.
 154. A pharmaceutical composition according toclaim 127 wherein R⁴⁷ and R⁴⁸ are independently selected from hydrogen,methyl and phenyl.
 155. A pharmaceutical composition according to claim127 wherein T is Hydrogen, C₁-C₆-alkyl optionally substituted with oneor more substituents independently selected from R⁵⁰, aryl,aryl-C₁-C₆-alkyl, heteroaryl, wherein the alkyl, aryl and heteroarylmoieties are optionally substituted with one or more substituentsindependently selected from R⁵⁰.
 156. A pharmaceutical compositionaccording to claim 155 wherein T is hydrogen, C₁-C₆-alkyl optionallysubstituted with one or more substituents independently selected fromR⁵⁰, ArG1, ArG1-C₁-C₆-alkyl, Het3, wherein the alkyl, aryl andheteroaryl moieties are optionally substituted with one or moresubstituents independently selected from R⁵⁰.
 157. A pharmaceuticalcomposition according to claim 156 wherein T is hydrogen, C₁-C₆-alkyl,optionally substituted with one or more substituents independentlyselected from R⁵⁰, phenyl, phenyl-C₁-C₆-alkyl, wherein the alkyl andphenyl moieties are optionally substituted with one or more substituentsindependently selected from R⁵⁰.
 158. A pharmaceutical compositionaccording to claim 157 wherein T is phenyl substituted with R⁵⁰.
 159. Apharmaceutical composition according to claim 127 wherein R⁵⁰ isC₁-C₆-alkyl, C₁-C₆-alkoxy, aryl, aryloxy, aryl-C₁-C₆-alkoxy,—C(═O)—NH—C₁-C₆-alkyl-aryl, —C(═O)—NR^(50A)—C₁-C₆-alkyl,—C(═O)—NH—(CH₂CH₂O)_(m)C₁-C₆-alkyl-COOH, heteroaryl, —C₁-C₆-alkyl-COOH,—O—C₁-C₆-alkyl-COOH, —S(O)₂R⁵¹, —C₂-C₆-alkenyl-COOH, —OR⁵¹, —NO₂,halogen, —COOH, —CF₃, —CN, ═O, —N(R⁵¹R⁵²), wherein the aryl orheteroaryl moieties are optionally substituted with one or more R⁵³.160. A pharmaceutical composition according to claim 159 wherein R⁵⁰ isC₁-C₆-alkyl, C₁-C₆-alkoxy, aryl, aryloxy, —C(═O)—NR^(50A)—C₁-C₆-alkyl,—C(═O)—NH—(CH₂CH₂O)_(m)C₁-C₆-alkyl-COOH, aryl-C₁-C₆-alkoxy , —OR⁵¹,—NO₂, halogen, —COOH, —CF₃, wherein any aryl moiety is optionallysubstituted with one or more R⁵³.
 161. A pharmaceutical compositionaccording to claim 160 wherein R⁵⁰ is C₁-C₆-alkyl, aryloxy,—C(═O)—NR^(51A)—C₁-C₆-alkyl, —C(═O)—NH—(CH₂CH₂O)_(m)C₁-C₆-alkyl-COOH,aryl-C₁-C₆-alkoxy , —OR⁵¹, halogen, —COOH, —CF₃, wherein any aryl moietyis optionally substituted with one or more R⁵³.
 162. A pharmaceuticalcomposition according to claim 161 wherein R⁵⁰ is C₁-C₆-alkyl, ArG1-O—,—C(═O)—NR^(50A)—C₁-C₆-alkyl, —C(═O)—NH—(CH₂CH₂O)_(m)C₁-C₆-alkyl-COOH,ArG1-C₁-C₆-alkoxy, —OR⁵¹, halogen, —COOH, —CF₃, wherein any aryl moietyis optionally substituted with one or more R⁵³.
 163. A pharmaceuticalcomposition according to claim 162 wherein R⁵⁰ is —C(═O)—NR^(50A)CH₂,—C(═O)—NH—(CH₂CH₂O)₂CH₂I—COOH, or —C(═O)—NR^(50A)CH₂CH₂.
 164. Apharmaceutical composition according to claim 162 wherein R⁵⁰ is phenyl,methyl or ethyl.
 165. A pharmaceutical composition according to claim164 wherein R⁵⁰ is methyl or ethyl.
 166. A pharmaceutical compositionaccording to claim 127 wherein m is 1 or
 2. 167. A pharmaceuticalcomposition according to claim 127 wherein R⁵¹ is methyl.
 168. Apharmaceutical composition according to claim 127 wherein R⁵³ isC₁-C₆-alkyl, C₁-C₆-alkoxy, —OR⁵¹, halogen,or —CF₃.
 169. A pharmaceuticalcomposition according to claim 127 wherein R^(50A) is —C(O)OCH₃,—C(O)OCH₂CH₃ —COOH, —CH₂C(O)OCH₃, —CH₂C(O)OCH₂CH₃, —CH₂CH₂C(O)OCH₃,—CH₂CH₂C(O)OCH₂CH₃, —CH₂COOH, methyl, or ethyl.
 170. A pharmaceuticalcomposition according to claim 127 wherein R^(50B) is —C(O)OCH₃,—C(O)OCH₂CH₃ —COOH, —CH₂C(O)OCH₃, —CH₂C(O)OCH₂CH₃, —CH₂CH₂C(O)OCH₃,—CH₂CH₂C(O)OCH₂CH₃, —CH₂COOH, methyl, or ethyl.
 171. A pharmaceuticalcomposition according to claim 1 wherein the zinc-binding ligand is

wherein V is C₁-C₆-alkyl, aryl, heteroaryl, aryl-C₁₋₆-alkyl- oraryl-C₂₋₄-alkenyl-, wherein the alkyl or alkenyl is optionallysubstituted with one or more substituents independently selected fromR⁵⁴, and the aryl or heteroaryl is optionally substituted with one ormore substituents independently selected from R⁵⁵, R⁵⁴ is independentlyselected from halogen, —CN, —CF₃, —OCF₃, aryl, —COOH and —NH₂, R⁵⁵ isindependently selected from hydrogen, halogen, —CN, —CH₂CN, —CHF₂, —CF₃,—OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —OS(O)₂CF₃, —SCF₃, —NO₂,—OR⁵⁶, —NR⁵⁶R⁵⁷, —SR⁵⁶, —NR⁵⁶S(O)₂R⁵⁷, —S(O)₂NR⁵⁶R⁵⁷, —S(O)NR⁵⁶R⁵⁷,—S(O)R⁵⁶, —S(O)₂R⁵⁶, —OS(O)₂ R⁵⁶, —C(O)NR⁵⁶R⁵⁷, —OC(O)NR⁵⁶R⁵⁷,—NR⁵⁶C(O)R⁵⁷, —CH₂C(O)NR⁵⁶R⁵⁷, —OC₁-C₆-alkyl-C(O)NR⁵⁶R⁵⁷, —CH₂OR⁵⁶,—CH₂OC(O)R⁵⁶, —CH₂NR⁵⁶R⁵⁷, —OC(O)R⁵⁶, —OC₁-C₈-alkyl-C(O)OR⁵⁶,—OC₁-C₆-alkyl-OR⁵⁶, —SC₁-C₆-alkyl-C(O)OR⁵⁶, —C₂-C₆-alkenyl-C(═O)OR⁵⁶,—NR⁵⁶—C(═O)—C₁-C₆-alkyl-C(═O)OR⁵⁶, —NR⁵⁶—C(═O)—C₁-C₆-alkenyl-C(═O)OR⁵⁶,—C(O)OR⁵⁶, or —C₂-C₆-alkenyl-C(═O)R⁵⁶, C₁-C₆-alkyl, C₂-C₆-alkenyl orC₂-C₆-alkynyl, which may optionally be substituted with one or moresubstituents selected from R⁵⁸, aryl, aryloxy, aryloxycarbonyl, aroyl,arylsulfanyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl,aroyl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl,heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl orheteroaryl-C₂-C₆-alkynyl, of which the cyclic moieties optionally may besubstituted with one or more substituents selected from R⁵⁹, R⁵⁶ and R⁵⁷are independently selected from hydrogen, OH, CF₃, C₁-C₁₂-alkyl,aryl-C₁-C₆-alkyl, —C(═O)—C₁-C₆-alkyl or aryl, wherein the alkyl groupsmay optionally be substituted with one or more substituentsindependently selected from R⁶⁰, and the aryl groups may optionally besubstituted with one or more substituents independently selected fromR⁶¹; R⁵⁶ and R⁵⁷ when attached to the same nitrogen atom may form a 3 to8 membered heterocyclic ring with the nitrogen atom, the heterocyclicring optionally containing one or two further heteroatoms selected fromnitrogen, oxygen and sulphur, and optionally containing one or twodouble bonds, R⁵⁸ is independently selected from halogen, —CN, —CF₃,—OCF₃, —OR⁵⁶, and —NR⁵⁶R⁵⁷, R⁵⁹ is independently selected from halogen,—C(O)OR⁵⁶, —CH₂C(O)OR⁵⁶, —CH₂OR⁵⁶, —CN, —CF₃, —OCF₃, —NO₂, —OR⁵⁶,—NR⁵⁶R⁵⁷ and C₁-C₆-alkyl, R⁶⁰ is independently selected from halogen,—CN, —CF₃, —OCF₃, —OC₁-C₆-alkyl, —C(O)OC₁-C₆-alkyl, —C(═O)—R⁶², —COOHand —NH₂, R⁶¹ is independently selected from halogen, —C(O)OC₁-C₆-alkyl,—COOH, —CN, —CF₃, —OCF₃, —NO₂, —OH, —OC₁-C₆-alkyl, —NH₂, C(═O) orC₁-C₆-alkyl, R⁶² is C₁-C₆-alkyl, aryl optionally substituted with one ormore substituents independently selected from halogen, or heteroaryloptionally substituted with one or more C₁-C₆-alkyl independently, orany enantiomer, diastereomer, racemic mixture, tautomer, or salt thereofwith a pharmaceutically acceptable acid or base.
 172. A pharmaceuticalcomposition according to claim 171 wherein V is aryl, heteroaryl, oraryl-C₁₋₆-alkyl-, wherein the alkyl is optionally substituted with oneor more substituents independently selected R⁵⁴, and the aryl orheteroaryl is optionally substituted with one or more substituentsindependently selected from R⁵⁵.
 173. A pharmaceutical compositionaccording to claim 172 wherein V is aryl, Het1, or aryl-C₁₋₆-alkyl-,wherein the alkyl is optionally substituted with one or moresubstituents independently selected from R⁵⁴, and the aryl or heteroarylmoiety is optionally substituted with one or more substituentsindependently selected from R⁵⁵.
 174. A pharmaceutical compositionaccording to claim 173 wherein V is aryl, Het2, or aryl-C₁₋₆-alkyl-,wherein the alkyl is optionally substituted with one or moresubstituents independently selected from R⁵⁴, and the aryl or heteroarylmoiety is optionally substituted with one or more substituentsindependently selected from R⁵⁵.
 175. A pharmaceutical compositionaccording to claim 174 wherein V is aryl, Het3, or aryl-C₁₋₆-alkyl-,wherein the alkyl is optionally substituted with one or moresubstituents independently selected from R⁵⁴, and the aryl or heteroarylmoiety is optionally substituted with one or more substituentsindependently selected from R⁵⁵.
 176. A pharmaceutical compositionaccording to claim 175 wherein V is aryl optionally substituted with oneor more substituents independently selected from R⁵⁵.
 177. Apharmaceutical composition according to claim 176 wherein V is ArG1optionally substituted with one or more substituents independentlyselected from R⁵⁵.
 178. A pharmaceutical composition according to claim177 wherein V is phenyl, naphthyl or anthranyl optionally substitutedwith one or more substituents independently selected from R⁵⁵.
 179. Apharmaceutical composition according to claim 178 wherein V is phenyloptionally substituted with one or more substituents independentlyselected from R⁵⁵.
 180. A pharmaceutical composition according to claim171 wherein R⁵⁵ is independently selected from halogen, C₁-C₆-alkyl,—CN, —OCF₃, —CF₃, —NO₂, —OR⁵⁶, —NR⁵⁶R⁵⁷, —NR⁵⁶C(O)R⁵⁷—SR⁵⁶,—OC₁-C₈-alkyl-C(O)OR⁵⁶, or —C(O)OR⁵⁶, C₁-C₆-alkyl optionally substitutedwith one or more substituents independently selected from R⁵⁸ aryl,aryl-C₁-C₆-alkyl, heteroaryl, or heteroaryl-C₁-C₆-alkyl of which thecyclic moieties optionally may be substituted with one or moresubstituents independently selected from R⁵⁹.
 181. A pharmaceuticalcomposition according to claim 180 wherein R⁵⁵ is independently selectedfrom halogen, C_(-C) ₆-alkyl, —CN, —OCF₃, —CF₃, —NO₂, —OR⁵⁶, —NR⁵⁶R⁵⁷,—NR⁵⁶C(O)R⁵⁷—SR⁵⁶, —OC₁-C₈-alkyl-C(O)OR⁵⁶, or —C(O)OR⁵⁶ C₁-C₆-alkyloptionally substituted with one or more substituents independentlyselected from R⁵⁸ ArG1, ArG1-C₁-C₆-alkyl, Het3, or Het3-C₁-C₆-alkyl ofwhich the cyclic moieties optionally may be substituted with one or moresubstituents independently selected from R⁵⁹.
 182. A pharmaceuticalcomposition according to claim 181 wherein R⁵⁵ is independently selectedfrom halogen, —OR⁵⁶, —NR⁵⁶R⁵⁷, —C(O)OR⁵⁶, —OC₁-C₈-alkyl-C(O)OR⁵⁶,—NR⁵⁶C(O)R⁵⁷ or C₁-C₆-alkyl.
 183. A pharmaceutical composition accordingto claim 182 wherein R⁵⁵ is independently selected from halogen, —OR⁵⁶,—NR⁵⁶R⁵⁷, —C(O)OR⁵⁶, —OC₁-C₈-alkyl-C(O)OR⁵⁶, —NR⁵⁶C(O)R⁵⁷, methyl orethyl.
 184. A pharmaceutical composition according to claim 171 whereinR⁵⁶ and R⁵⁷ are independently selected from hydrogen, CF₃, C₁-C₁₂-alkyl,or —C(═O)—C₁-C₆-alkyl; R⁵⁶ and R⁵⁷ when attached to the same nitrogenatom may form a 3 to 8 membered heterocyclic ring with the nitrogenatom.
 185. A pharmaceutical composition according to claim 184 whereinR⁵⁶ and R⁵⁷ are independently selected from hydrogen or C₁-C₁₂-alkyl,R⁵⁶ and R⁵⁷ when attached to the same nitrogen atom may form a 3 to 8membered heterocyclic ring with the nitrogen atom.
 186. A pharmaceuticalcomposition according to claim 185 wherein R⁵⁶ and R⁵⁷ are independentlyselected from hydrogen or methyl, ethyl, propyl butyl, R⁵⁶ and R⁵⁷ whenattached to the same nitrogen atom may form a 3 to 8 memberedheterocyclic ring with the nitrogen atom.
 187. A pharmaceuticalcomposition according to claim 1 wherein the zinc-binding ligand is

wherein M is C₁-C₆-alkyl, aryl, heteroaryl, aryl-C₁₋₆alkyl- oraryl-C₂₋₄-alkenyl-, wherein the alkyl or alkenyl is optionallysubstituted with one or more substituents independently selected fromR⁶³, and the aryl or heteroaryl is optionally substituted with one ormore substituents independently selected from R⁶⁴, R⁶³ is independentlyselected from halogen, —CN, —CF₃, —OCF₃, aryl, —COOH and —NH₂, R⁶⁴ isindependently selected from hydrogen, halogen, —CN, —CH₂CN, —CHF₂, —CF₃,—OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —OS(O)₂CF₃, —SCF₃, —NO₂,—OR⁶⁵, —NR⁶⁵R⁶⁶, —SR⁶⁵, —NR⁶⁵S(O)₂R⁶⁶, —S(O)₂NR⁶⁵R⁶⁶, —S(O)NR⁶⁵R⁶⁶,—S(O)R⁶⁵, —S(O)₂R⁶⁵, —C(O)NR⁶⁵R⁶⁶, —OC(O)NR⁶⁵R⁶⁶, —NR⁶⁵C(O)R⁶⁶,—CH₂C(O)NR⁶⁵R⁶⁶, —OC₁-C₆-alkyl-C(O)NR⁶⁵R⁶⁶, —CH₂OR⁶⁵, —CH₂OC(O)R⁶⁵,—CH₂NR⁶⁵R⁶⁶, —OC(O)R⁶⁵, —OC₁C₆-alkyl-C(O)OR⁶⁵, —OC₁-C₆-alkyl-OR⁶⁵,—SC₁-C₆-alkyl-C(O)OR⁶⁵, —C₂-C₆-alkenyl-C(═O)OR⁶⁵,—NR⁶⁵—C(═O)—C₁-C₆-alkyl-C(═O)OR⁶⁵, —NR⁶⁵—C(═O)-C₁-C₆-alkenyl-C(═O)OR⁶⁵,—C(O)OR⁶⁵, or —C₂-C₆-alkenyl-C(═O)R⁶⁵, C₁-C₆-alkyl, C₂-C₆-alkenyl orC₂-C₆-alkynyl, each of which may optionally be substituted with one ormore substituents selected from R⁶⁷, aryl, aryloxy, aryloxycarbonyl,aroyl, arylsulfanyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl,aryl-C₂-C₆-alkenyl, aroyl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl,heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl orheteroaryl-C₂-C₆-alkynyl, of which the cyclic moieties optionally may besubstituted with one or more substituents selected from R⁶⁸, R⁶⁵ and R⁶⁶are independently selected from hydrogen, OH, CF₃, C₁-C₁₂-alkyl,aryl-C₁-C₆-alkyl, —C(═O)—R⁶⁹, aryl or heteroaryl, wherein the alkylgroups may optionally be substituted with one or more substituentsselected from R⁷⁰, and the aryl and heteroaryl groups may optionally besubstituted with one or more substituents independently selected fromR⁷¹; R⁶⁵ and R⁶⁶ when attached to the same nitrogen atom may form a 3 to8 membered heterocyclic ring with the said nitrogen atom, theheterocyclic ring optionally containing one or two further heteroatomsselected from nitrogen, oxygen and sulphur, and optionally containingone or two double bonds, R⁶⁷ is independently selected from halogen,—CN, —CF₃, —OCF₃, —OR , and —NR⁶⁵R⁶⁶, R⁶⁸ is independently selected fromhalogen, —C(O)OR⁶⁵, —CH₂C(O)OR⁶⁵, —CH₂OR⁶⁵, —CN, —CF₃, —OCF₃, —NO₂,—OR⁶⁵, —NR⁶⁵R⁶⁶ and C₁-C₆-alkyl, R⁶⁹ is independently selected fromC₁-C₆-alkyl, aryl optionally substituted with one or more halogen, orheteroaryl optionally substituted with one or more C₁-C₆-alkyl, R⁷⁰ isindependently selected from halogen, —CN, —CF₃, —OCF₃, —OC₁-C₆-alkyl,—C(O)OC₁-C₆-alkyl, —COOH and —NH₂, R⁷¹ is independently selected fromhalogen, —C(O)OC₁-C₆-alkyl, —COOH, —CN, —CF₃, —OCF₃, —NO₂, —OH,—OC₁-C₆-alkyl, —NH₂, C(═O) or C₁-C₆-alkyl, or any enantiomer,diastereomer, racemic mixture, tautomer, or salt thereof with apharmaceutically acceptable acid or base.
 188. A pharmaceuticalcomposition according to claim 187 wherein M is aryl, heteroaryl oraryl-C₁₋₆alkyl-, wherein the alkyl is optionally substituted with one ormore R⁶³, and the aryl or heteroaryl is optionally substituted with oneor more substituents independently selected from R⁶⁴.
 189. Apharmaceutical composition according to claim 188 wherein M is aryl orheteroaryl optionally substituted with one or more substituentsindependently selected from R⁶⁴.
 190. A pharmaceutical compositionaccording to claim 189 wherein M is ArG1 or Het1 optionally substitutedwith one or more substituents independently selected from R⁶⁴.
 191. Apharmaceutical composition according to claim 190 wherein M is ArG1 orHet2 optionally substituted with one or more substituents independentlyselected from R⁶⁴.
 192. A pharmaceutical composition according to claim191 wherein M is ArG1 or Het3 optionally substituted with one or moresubstituents independently selected from R⁶⁴.
 193. A pharmaceuticalcomposition according to claim 192 wherein AA is phenyl, naphtyl,anthryl, carbazolyl, thienyl, pyridyl, or benzodioxyl optionallysubstituted with one or more substituents independently selected fromR⁶⁴.
 194. A pharmaceutical composition according to claim 193 wherein Mis phenyl or naphtyl optionally substituted with one or moresubstituents independently selected from R⁶⁴.
 195. A pharmaceuticalcomposition according to claim 187 wherein R⁶⁴ is independently selectedfrom hydrogen, halogen, —CF₃, —OCF₃, —OR⁶⁵, —NR⁶⁵R⁶⁶, C₁-C₆-alkyl,—OC(O)R⁶⁵, —OC₁-C₆-alkyl-C(O)OR⁶⁵, aryl-C₂-C₆-alkenyl, aryloxy or aryl,wherein C₁-C₆-alkyl is optionally substituted with one or moresubstituents independently selected from R⁶⁷, and the cyclic moietiesoptionally are substituted with one or more substituents independentlyselected from R⁶⁸.
 196. A pharmaceutical composition according to claim195 wherein R⁶⁴ is independently selected from halogen, —CF₃, —OCF₃,—OR⁶⁵, —NR⁶⁵R⁶⁶, methyl, ethyl, propyl, —OC(O)R⁶⁵, —OCH₂—C(O)OR⁶⁵,—OCH₂—CH₂—C(O)OR⁶⁵, phenoxy optionally substituted with one or moresubstituents independently selected from R⁶⁸.
 197. A pharmaceuticalcomposition according to claim 187 wherein R⁶⁵ and R⁶⁶ are independentlyselected from hydrogen, CF₃, C₁-C₁₂-alkyl, aryl, or heteroaryloptionally substituted with one or more substituents independentlyselected from R⁷¹.
 198. A pharmaceutical composition according to claim197 wherein R⁶⁵ and R⁶⁶ are independently hydrogen, C₁-C₁₂-alkyl, aryl,or heteroaryl optionally substituted with one or more substituentsindependently selected from R⁷¹.
 199. A pharmaceutical compositionaccording to claim 198 wherein R⁶⁵ and R⁶⁶ are independently hydrogen,methyl, ethyl, propyl, butyl, 2,2-dimethyl-propyl, ArG1 or Het1optionally substituted with one or more substituents independentlyselected from R⁷¹.
 200. A pharmaceutical composition according to claim199 wherein R⁶⁵ and R⁶⁶ are independently hydrogen, methyl, ethyl,propyl, butyl, 2,2-dimethyl-propyl, ArG1 or Het2 optionally substitutedwith one or more substituents independently selected from R⁷¹.
 201. Apharmaceutical composition according to claim 200 wherein R⁶⁵ and R⁶⁶are independently hydrogen, methyl, ethyl, propyl, butyl,2,2-dimethyl-propyl, ArG1 or Het3 optionally substituted with one ormore substituents independently selected from R⁷¹.
 202. A pharmaceuticalcomposition according to claim 201 wherein R⁶⁵ and R⁶⁶ are independentlyhydrogen, methyl, ethyl, propyl, butyl, 2,2-dimethyl-propyl, phenyl,naphtyl, thiadiazolyl optionally substituted with one or more R⁷¹independently; or isoxazolyl optionally substituted with one or moresubstituents independently selected from R⁷¹.
 203. A pharmaceuticalcomposition according to claim 187 wherein R⁷¹ is halogen orC₁-C₆-alkyl.
 204. A pharmaceutical composition according to claim 203wherein R⁷¹ is halogen or methyl.
 205. A pharmaceutical compositionaccording to claim 1 wherein the insulin is rapid acting insulin.
 206. Apharmaceutical composition according to claim 1 wherein the insulin isselected from the group consisting of human insulin, an analoguethereof, a derivative thereof, and combinations of any of these.
 207. Apharmaceutical composition according to claim 206 wherein the insulin isan analogue of human insulin selected from the group consisting of iii.An analogue wherein position B28 is Asp, Lys, Leu, Val, or Ala andposition B29 is Lys or Pro; and iv. des(B28-B30), des(B27) or des(B30)human insulin.
 208. A pharmaceutical composition according to claim 207,wherein the insulin is an analogue of human insulin wherein position B28is Asp or Lys, and position B29 is Lys or Pro.
 209. A pharmaceuticalcomposition according to claim 207 wherein the insulin is des(B30) humaninsulin.
 210. A pharmaceutical composition according to claim 207wherein the insulin is is an analogue of human insulin wherein positionB3 is Lys and position B29 is Glu or Asp.
 211. A pharmaceuticalcomposition according to claim 206 wherein the insulin is a derivativeof human insulin having one or more lipophilic substituents.
 212. Apharmaceutical composition according to claim 211 wherein the insulinderivative is selected from the group consisting ofB29-N^(ε)-myristoyl-des(B30) human insulin, B29-N^(ε)-palmitoyl-des(B30)human insulin, B29-N^(ε)-myristoyl human insulin, B29-N^(ε)-palmitoylhuman insulin, B28-N^(ε)-myristoyl Lys^(B28) Pro^(B29) human insulin,B28-N^(ε)-palmitoyl Lys^(B28) Pro^(B29) human insulin,B30-N^(ε)-myristoyl-Thr^(B29)Lys^(B30) human insulin,B30-N^(ε)-palmitoyl-Thr^(B29)Lys^(B30) human insulin,B29-N^(ε)—(N-palmitoyl-γ-glutamyl)-des(B30) human insulin,B29-N^(ε)—(N-lithocholyl-γ-glutamyl)-des(B30) human insulin,B29-N^(ε)-(ω-carboxyheptadecanoyl)-des(B30) human insulin andB29-N^(ε)-(ω-carboxyheptadecanoyl) human insulin.
 213. A pharmaceuticalcomposition according to claim 212 wherein the insulin derivative isB29-N^(ε)-myristoyl-des(B30) human insulin.
 214. A pharmaceuticalcomposition according to claim 1 comprising 2-6 moles zinc²⁺ ions permole insulin.
 215. A pharmaceutical composition according to claim 214comprising 2-3 moles zinc²⁺ ions per mole insulin.
 216. A pharmaceuticalcomposition according to claim 1 further comprising at least 3 moleculesof a phenolic compound per insulin hexamer.
 217. A pharmaceuticalcomposition according to claim 1 further comprising an isotonicityagent.
 218. A pharmaceutical composition according to claim 1 furthercomprising a buffer substance.
 219. A method of stabilising an insulincomposition comprising adding a zinc-binding ligand according to claim 1to the insulin composition.
 220. A method of treating type 1 or type 2diabetes comprising administering to a patient in need thereof apharmaceutically effective dose of an insulin composition according toclaim 1.